Abstract
Infectious diseases still pose one of the leading causes of morbidity and mortality in the world, and the problem of antimicrobial resistance is becoming more and more dangerous to the health of global populations. Multidrug-resistant (MDR) bacteria have emerged rapidly, and this has become a cause of concern among international health organizations and government agencies such as the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). The scarcity of the emergence of new antimicrobial agents and the decreasing efficacy of the current antibiotics predominantly cause this crisis. The mechanisms of bacterial resistance are varied and some of them include enzyme inactivation, low-membrane permeability, target site protection or alteration, target overexpression, structural changes of the enzymes or cellular structures, and increased efflux through overexpressed efflux pumps. Due to their distinctive physicochemical characteristics, nanoparticles have become the potentially promising antimicrobial agents that can either work alone or serve as the carriers of antimicrobial agents without necessarily undergoing the standard mechanisms of resistance. Nanoparticle categories, such as metallic, organic, carbon-based, and hybrid systems have proved to be very effective with regard to antibacterial activity against MDR pathogens. Moreover, nanoparticles are under investigation in combination with plant-derived antimicrobials to improve the ability and minimize the toxicity. Recent methods of using nanoparticles are biofilm disruption, quorum sensing, plasmid eradication, efflux pump, and synergist antimicrobial combinations. Irrespective of these improvements, there are safety, biocompatibility, scalability, and environmental impact issues. This review comprises newly developed developments in nanoparticle-based approaches to addressing drug-resistant bacteria and addresses their clinical translation possibilities.
Keywords: Nanoparticles, Multi-drug resistance bacteria, Protein channels, Antibiotics
Introduction
Modern medicine would not be where it is today without antibiotics, which have revolutionized the treatment of bacterial infections. Unfortunately, the extensive and careless use of antibiotics in the past has led to the fast emergence of dangerous bacteria with antimicrobial resistance (AMR). Not every strain of bacteria responds to standard therapy [1]. Since people with viral disorders are increasingly using antibiotics for secondary infections, the current COVID-19 pandemic is expected to cause this figure to rise even further [2]. In order to fight antimicrobial resistance, creative solutions are essential. In the battle against AMR, nanotechnology presents exciting new possibilities. Because they get beyond traditional bacterial defense systems, nanoparticles’ antibacterial qualities are unique. Because of their multivalence and nanoscale molecular confinement, which provide strong interactions and a high surface-area-to-volume ratio, nanoparticles are primarily useful as therapeutic agents [3]. The antibacterial properties of organic nanoparticles, metal oxides, nanoscaled metals, and nanocomposites are high, and it is possible to use them successfully to control surface infections and infectious diseases [4]. Various antibacterial nanomaterials (also referred to as nanobiotics) act against their target bacteria differently due to their different chemical compositions and intrinsic characteristics. The sensitivity of the microbes to certain nanomaterials changes largely during the physiological life cycle that involves the planktonic, biofilm, stationary, nutrient-deprived, and logarithmic stages [5]. The antibacterial activity of nanomaterials is influenced by oxygen levels, pH, temperature, among others. The special properties of nanobiotics contribute to the creation of modern methods of treatment, which would be able to effectively and correctly address the bacterial systems [6]. This review evaluates AMR and gives a thorough examination of nanoparticles to fight AMR, with a special concentration on the action mechanism of nanobiotics [7]. We also explore the potential of functional nanoparticles as vaccines and discuss the challenges involved in developing new antibiotics.
Rise of AMR
Antimicrobial resistance has attracted significant global health issues since the extraordinary ability of microorganisms, especially bacteria, to evolve in response to the selection pressure exerted by antimicrobial drugs [8]. This marked one of the turning points in medical history. Regrettably, this success has been a factor in the rise in AMR. The majority of hospital settings occasionally experience errors regarding medication administration and also cross-contamination, which makes it more likely that nosocomial infections will become resistant to general treatments. There are many ways in which AMR may develop. There are changes in the targets of antibiotics, active excretion of antibiotics through the cell, diminishing drug uptake, and enzymatic loss of antibiotics [9]. Target modification is an example of genetic modifications in bacteria that cause a sensitivity alteration to antibiotics. Reduction in antibiotic penetration can also be done by altering the permeability of cell wall or outer membrane. The formation of biofilms increases the complexity of the treatment process, since microorganisms can seek shelter in them, which is a defensive cavity [10]. Initially, there is a reduction in the population of susceptible microorganisms that exhibit low resistance to antimicrobial agents [11]. Antimicrobial treatments kill most of the susceptible microbes on exposure, and only a minor percentage develop resistance [12]. Because antimicrobial therapies eradicate vulnerable pathogens, resistant strains are more likely to survive and proliferate, especially in favorable environments [13]. The prevalence of resistant strains in the microbial community rises as a result of this selection pressure [14].
A second critical aspect of resistance propagation is the dissemination of resistance traits. Antibiotic resistance genes can be transferred from infected pathogens to neighboring microorganisms. Each infectious agent evolves through these mechanisms. Every bacterium in the system undergoes transformation and ultimately acquires resistance to antibiotics. To lower the incidence of antibiotic resistance and maintain the efficacy of existing antimicrobials, a thorough and prompt approach is necessary [15]. Natural selection, horizontal gene transfer, and genetic mutations interact intricately to produce this occurrence. Bacteria have quickly evolved and propagated resistance mechanisms because of their genetic flexibility [16]. Natural selection, horizontal gene transfer, and mutation all contribute to the development of resistance. The rise of microorganisms that are resistant to drugs makes the issue worse. Due to the pharmaceutical industry’s decreasing investment returns in antibiotic research and development as well as the inadequate creation of new medications, AMR is getting worse [17].
Consequences of AMR for healthcare
AMR has far-reaching and significant consequences for public health, healthcare institutions, and the economy. Substantial evidence shows that AMR is negatively impacting healthcare systems worldwide [18]. As a chronic global public health crisis, by 2050, AMR is expected to kill 10 million people a year. In the United States alone, antibiotic-resistant infections result in an estimated $35 billion in lost productivity and $20 billion in additional medical expenditures each year [19]. These impacts stem directly from antimicrobial resistance. Healthcare work and resources become more burdened when patients with antibiotic-resistant bacteria require more prolonged hospitalization and more complicated treatment [20]. AMR is rendering the traditional medical treatments ineffective, adding more risks to the lives of the individuals who have gone through surgical operations such as organ transplants, chemotherapy, and surgery [19]. Antibiotic resistance is an increasingly urgent global health concern as the problem continues to spread worldwide. Due to their damaged immune systems and restricted treatment choices, immunocompromised populations, such as those with cancer, SARS-CoV-2, or HIV [21–25], are especially susceptible to AMR [26].
Multidrug resistance (MDR) is a significant issue that impacts the outcomes of the healthcare system and patient health, as it causes antibiotic resistance and restricts the quantity of available options. Since the infections are increasingly becoming difficult to treat, patients end up spending more time in hospitals, with the net effect of raising the cost of treatment, in addition to putting a strain on the healthcare facilities. MDR also promotes the dissemination of AMR genes, which enables the spread of resistance among microorganisms to a greater extent. In the end, the increased morbidity and higher death rate are the results of these reasons, and multidrug resistance becomes one of the significant global public health problems, as shown in Fig. 1.
Fig. 1.
The clinical and public health implications of MDR of bacterial pathogens. MDR leads to failure in antibiotic therapy, lack of therapeutic choices, high health care cost, long hospitalizations, spread of AMR genes and high mortality rates
Finding fresh approaches to fight AMR is urgent
The creation of novel approaches to fight AMR, is a pressing problem that has to be addressed right now. AMR has been recognized by the World Health Organization (WHO) as a danger to world health [27]. One objective of the Antimicrobial Resistance National Action Plans, which member nations are encouraged to adopt under the WHO’s Global Action Plan, is to reduce antibiotic use in livestock, agricultural production, and human consumption. The “One Health immediate and coordinated action to address AMR is necessary since current approaches do not adequately include multi-sectoral and cross-disciplinary activities. Animals, people, and the environment are all impacted by the inappropriate use of antibiotics. This issue is being tackled through the One Health framework [28]. If current trends continue, conventional medical therapies may pose hazards, and common diseases could become incurable. Urgent and innovative measures are necessary to combat AMR. A comprehensive and multifaceted strategy is required, including healthcare antibiotic stewardship programs, CRISPR-Cas gene editing, phage therapy, and the use of probiotics and microbiome modulation to enhance innate defenses [29]. Overcoming resistance requires the creation of new immunotherapies, the use of nanotechnology for targeted drug delivery, and the combination of various therapies [30, 31]. Effectively and sustainably addressing AMR requires public education, a One Health approach, and global surveillance. A novel strategy to stop the transmission of viruses and bacteria resistant to antibiotics is provided by nanomedicine [32]. Specific delivery of drugs minimizes the chances of germs developing resistance since the medication is concentrated in the affected region. Nanotechnology can be used to revolutionize the battle against infectious diseases and enhance drug efficacy. This highlights the need to consider the potential of this innovative technology to improve healthcare delivery. This paper will examine the developments of this area and how it could help combat AMR and its incidence on the world health [19].
Types and formulations of nanoparticles
Organic NPs
Organic nanoparticles (NPs) are nanoparticles that are primarily consisting of organic components (polymers, lipids, proteins or carbon-compounds), and that have been of special interest in biomedical biomarkers due to their biocompatibility as well as to their greatest structural flexibility. Compared to metallic nanoparticles, organic NPs can easily be manipulated to entrap, shield, and present antimicrobial agents in order to enhance stability of drugs, solubility and targeted delivery [33]. Recent publications indicate that organic NPs can increase antimicrobial performance by promoting the controlled drug release, bacterial membrane disruption, and biofilm penetration. They are also amenable to surface functionalization with ligands or biomolecules to aid targeted interaction with a specific pathogen as well as reduced toxicity to host cells, which has been of direct interest in more current antimicrobial and drug-delivery studies [34].
Extensive research has been conducted on various organic nanoparticles in recent years. The first nanoscale medications approved for human use were liposomes. Because liposomes are non-toxic, biocompatible, and biodegradable, they are not harmful to living things [35]. They are composed of a core that contains either hydrophilic or hydrophobic medications, surrounded by one or more lipid layers. Encapsulated hydrophilic antibacterial medicines are shielded from in vivo degradation by the liposomal nanoparticle core’s significant drug-loading capability [36, 37]. In order to prevent and cure both acute and chronic respiratory tract infections, Bassetti et al. examined the therapeutic effectiveness of aerosolised liposomal antimicrobials, including ciprofloxacin, tobramycin, amphotericin B, and amikacin [38]. Different monomers combine to generate polymer-based organic nanoparticles, which have distinctive structural topologies for drug delivery. Dendrimers, for instance, are micro-aggregates created when polymers self-assemble into a three-dimensional branching structure, whereas lactic and glycollic acids copolymerise to create polylactic-co-glycolic acid (PLGA) [39, 40].
Inorganic nanoparticles
Inorganic nanoparticles are made out of metals, metal Oxides or semiconductor materials and have been extensively studied to investigate their high antimicrobial strengths and inherent abilities. The nanoparticles can deactivate the microorganisms in various ways, which include the generation of reactive oxygen species, the release of metal ions, and direct disorientation of the bacterial cell membrane. Inorganic nanoparticles are especially effective against multidrug-resistant pathogens, given their high stability and multifunctional mode of action. They can also be optimized to have tunable physicochemical properties for selected biomedical and antimicrobial applications. Metal nanoparticles and metal oxide nanoparticles are two types of inorganic nanoparticles. They have unique antimicrobial qualities. They can be used separately or in conjunction with antibiotics to create dual mechanisms because of their unique antibacterial qualities [41, 42].
Strategies of nanoparticle-drug interaction and nano-finding materials with antibacterial properties. Various ways of incorporating or attaching active agents to nanocarriers, such as to liposomes, polymeric nanoparticles, dendrimers, and adsorbing onto nanoparticles, are depicted; all of these improve drug stability, controlled release, and targeted delivery to microbial cells. Diverse inorganic and carbon-based nanomaterials (e.g., metallic nanoparticles, single-walled carbon nanotubes, and carbon nanostructures) are shown in contact with bacteria, causing bacterial death by engaging in different processes (e.g., membrane disruption, oxidative stress, and interference with cellular processes). Comprehensively, the Fig. 2 serves to identify the role of design of nanocarriers and inherent antimicrobial characteristics of nanomaterials in the increased antimicrobial activity.
Fig. 2.
Diagrammatic illustration of nanotechnology-based antimicrobial applications strategies. The left panel shows various nanoparticle delivery systems, such as liposomes, polymeric nanoparticles, dendrimers and adsorption-based encapsulation. The right panel illustrates different nanomaterials like metallic nanoparticles and carbon nanostructures, that lead to the killing mechanisms of bacteria
Hybrid NPs.
A composite drug delivery approach utilizes hybrid nanoparticles, including both organic and inorganic varieties. This combination approach enhances treatment effectiveness while reducing toxicity and resistance by augmenting biological properties. Lipid-polymer hybrid nanoparticles consist of a lipid exterior and a polymeric inside. These hybrid nanoparticles have shown efficacy as a medication delivery system [43]. These hybrid nanoparticles integrate the beneficial characteristics of lipids and polymers, exhibiting biocompatibility, structural rigidity, and prolonged drug release. This kind may enhance medicine targeting and release by encapsulating both hydrophobic and hydrophilic drugs [44, 45]. A recent research reveals that polymer gold (AuNP) may facilitate the hybridization process. He X et al. examine the effectiveness of a polyhexamethylenebiguanide polymer hybridized with gold nanoparticles as a drug delivery system and discover that it enhances the healing of Staphylococcus aureus wounds synergistically [46].
To increase the adherence of Ag nanoparticles, a matrix was created by combining magnetic carboxymethyl cellulose with poly-lysine. This hybrid Ag NP complex is very effective against S and has a synergistic antibacterial action. aureus as well as E. coli, which makes it a desirable choice for treating wound infections [47].
Nanoantibiotic vs. free antibiotic
When used properly, antibiotics can prevent the spread of illness, stop the development of germs, and even save lives. In treating infections produced by planktonic organisms or biofilms, they constitute the primary pharmacological options. Synthetic antibiotic molecules with an average one-dimensional diameter of no less than 100 nm or manufactured nanoparticles (NPs) including antibiotic molecules are collectively referred to as “nonoantibiotics” (nAbts) [48]. Antibiotics efficiently target bacteria by interfering with critical bacterial activities, including as proton transport across cell membranes, energy generation and storage, protein synthesis, and the integrity of cell wall components [49]. Multifunctional “intelligent” antimicrobials included in nanoparticles enhance drug delivery to specific sites and facilitate membrane permeability by interacting with bacterial cell walls and membranes upon activation. nAbts need just a single dosage to achieve target-specific controlled release, in contrast to the several doses necessary for systemic release by most conventional antibiotics [50].
Contrary to the case of free antibiotics, delivery systems based on nanoparticles have multiple advantages, such as accurate targeting of certain locations within bacterial cells, enhanced therapeutic efficacy through controlled release, less dosage and administration rate.
Since nanoparticles (NPs) have much higher surface and volume ratios, their contact area is much greater than that of molecular materials [51]. Nanoparticles enable the targeted administration of medications while simultaneously triggering several antibacterial processes. Consequently, NPs have enhanced effectiveness against MDR strains in comparison to monotherapy or combination therapies [52]. Microorganisms may be eliminated by various processes by β-lactam antibiotics and β-lactam non-antibiotics, for instance. A method to impede the transpeptidase enzyme from cross-linking peptidoglycan in bacterial cell walls is to restrict its activity [53]. Another way is impeding peptidoglycan production in bacterial cell walls by reducing the function of penicillin-binding proteins (PBPs). Furthermore, β-lactam antibiotics eradicate FtsI (PBP3), an essential protein complex vital for bacterial viability [54]. Reactive oxygen species (ROS) produced by nAbts have been connected in certain studies to membrane dysfunction, DNA damage, protein denaturation, and reduced membrane stability. Nanoparticles linked to antibiotics, upon decomposition and subsequent release of metal ions, constitute a biomechanical threat to cells [55]. Protein regulation, lipid and carbohydrate metabolism, energy metabolism, bacterial growth suppression, and cellular death are all impacted by the inhibition of ATPase and the binding of ribosomal subunits to tRNA during signal transduction [56, 57]. The interaction between nanosized antibiotics and bacterial intracellular components is essential for several activities, including antimicrobial administration, drug transport pathways, cellular localization, and the interruption of protein synthesis [57, 58]. In light of the growing problem of antibiotic resistance, nAbts are being evaluated as a possible alternative to current therapies for clinical infections [59, 60].
Nanoparticle (NP) mechanisms of action
The exact mechanisms of action are difficult to determine due to the complexity of NP activity. Nanoparticles may eradicate bacteria via many ways, including interacting with DNA and ribosomes, breaking cell walls and membranes, and enhancing drug administration by membrane fusion [61, 62]. Electrostatic attractions, receptor-ligand interactions, hydrophobic interactions, and Van der Waals forces are some of the factors that affect the unique physicochemical properties of nanomaterials, including their ability to chelate with bacterial cells [63].
Cell wall and Cell membrane destruction
As a physical defence mechanism, bacterial cell walls have evolved resistance to antimicrobials. Teichoic acids and lipopolysaccharide are phosphate or carboxyl groups found on the outer membranes of Gram-positive and Gram-negative bacteria, respectively, that give the bacterium’s surface a negative charge. Because they can’t cross membranes, hydrophobic antimicrobials don’t work as well against bacteria in this very polar environment [63, 64]. In the end, poor energy transfer and cellular death result from membrane depolarisation, decreased permeability, and decreased fluidity caused by electrostatic adsorption to the cell wall [65].
Another consequence of nanoparticle aggregation is the creation of “pits” in the bacterial cell wall. They therefore provide a danger of entering cells, changing their membranes, causing structural damage, and eventually killing cells. By interacting with the negative charges on bacterial surfaces, namely through carboxyl or phosphate groups, positively charged ions generated by nanoparticles intensify their bactericidal activity. Because of their thick peptidoglycan coating, nanoparticles (NPs) are unable to enter Gram-positive bacterial cells. NPs have only been observed on bacterial surfaces thus far [66]. The substantial peptidoglycan layer of Gram-positive bacteria obstructs the infiltration of NPs, into these cells. As a result, NPs mostly interact with the surfaces of bacteria. Silver, gold, copper, silicon, nickel, and selenium are among the metal elements and metal oxides that have been shown to have antibacterial qualities. Zinc oxide (ZnO), titanium dioxide (TiO2), copper oxide (CuO), magnesium oxide (MgO), and silicon dioxide (SiO2) are examples of metal oxides. Because of their higher surface area-to-volume ratio, organic nanoparticles are superior than inorganic ones; nonetheless, they frequently show inadequate biocompatibility and biodegradability, which might be troublesome [67]. The size and charge of inorganic nanoparticles influence their potential cytotoxicity, which is also dose-dependent. Because of their special chemical, physical, and biological characteristics, carbon nanotubes, cylindrical carbon structures with diameters usually in the nanometre range, have a great deal of potential for drug delivery. Mesoporous nanoparticle carriers, composed of silica, possess a large surface area, strong structure, and high porosity. The porous nature of this material, characterized by numerous internal voids, allows it to contain a high concentration of antimicrobials [68].
Nanoparticles disable efflux pumps to restore antibiotic activity. In essence, nanomaterials can circumvent or inhibit bacterial efflux systems by multiple routes. Some metal NPs (Ag, Cu, Zn, etc.) bind or block pump proteins directly as competitive substrates, while others disrupt the membrane or dissipate the proton-motive force, crippling pump function. Nanocarriers (liposomes or polymeric NPs) can encapsulate antibiotics and deliver them into cells (a “Trojan horse”), effectively bypassing efflux export. Additionally, certain NPs downregulate efflux gene expression. For example, TiO2 NPs significantly lowered mexA/B/Y efflux gene transcripts in P. aeruginosa, and green-synthesized AuNPs reduced mexA/mexB levels in P. aeruginosa. Together these actions raise intracellular drug levels and enhance killing (sometimes also reducing biofilm formation) [69, 70].
Reactive oxygen species (ROS) production
Oxidative metabolism results in reactive oxygen species (ROS). They control signals related to growth, survival, and apoptosis. They also have a significantly higher positive redox potential. Hydroxyl radicals (OH), superoxide radicals (O2−), singlet oxygen (O2), and hydrogen peroxide (H2O2) are examples of reactive oxygen species (ROS) [58, 71]. Different combinations of reactive oxygen species are produced by different nanoparticles, each of which exhibits unique antibacterial properties [66]. While MgO and ZnO nanoparticles only create superoxide radicals (O2-) and a combination of hydrogen peroxide (H2O2) and hydroxyl (OH) radicals, respectively, Ag and Cu nanoparticles produce a variety of reactive oxygen species (ROS) [72]. In the event of reactive oxygen species, they are largely generated by two sources natural products and respiratory chai perturbation. Reduced glutathione is a technique employed by scavengers to have low levels of these compounds [67].
The generation and removal of reactive oxygen species (ROS) in a natural ecosystem is normally in equilibrium. However, when extreme stress occurs, reactive oxygen species (ROS) overload will develop and damage the microorganisms, or disrupt the integrity of the cell membrane [73]. When combined with oxidative stress, reactive oxygen species (ROS) damage intracellular macromolecules, resulting in lipid peroxidation, protein modification, enzyme inhibition, disruption of the electron transport chain, and damage to RNA or DNA.
Silver (Ag), copper (Cu), zinc oxide (ZnO), titanium dioxide (TiO2), and iron (Fe NPs) are examples of nanoparticles (NPs) that produce reactive oxygen species (ROS) and have strong antibacterial properties [74, 75].
Attaching to and endangering an intracellular component
Bacterial function and viability depend on intracellular signaling networks and bacterial cellular homeostasis. The possibility of cellular death arises when nanomaterials are modified to obstruct certain routes. Mistakes in gene expression, DNA damage, and protein synthesis are all instances of disruptions [76, 77]. One example is the creation of pyrimidine-capped AuNPs (Au-DAPT), which is accomplished by adding 4,6-diamino-2-pyrimidinethiol (DAPT), a 2-pyrimidinethiol derivative found in E. coli, to AuNPs. These nanoparticles prevent even drug-resistant bacteria, such Pseudomonas aeruginosa and Escherichia coli, from proliferating [56]. Biofilm can be broken down by NPs due to their great penetrating capability. After passing through the extracellular polysaccharide matrix of the biofilm, they engage in bactericidal interactions with the bacteria. The way NPs interact with and penetrate biofilm is significantly influenced by their charge. Cationic NPs, for example, interact strongly with anionic matrices because to their positive charge [78, 79].
Nanoantibiotics’ synergistic activity
Antibiotics, whether coupled with or integrated into nanoparticles, render them resistant to the enzymes and chemicals that would ordinarily degrade them. This barrier may enhance a drug’s therapeutic effectiveness. A dose reduction is crucial to improve therapeutic efficacy and reduce host risk [80–82]. By implementing treatments that stimulate diverse processes and concentrating on cargo release, bacteria are protected from exposure to sub-minimal inhibitory doses of the drug, while nanocarriers enhance the penetration of antibiotics through bacterial cell walls [83]. This thus diminishes resistance selection. The antibiotic-induced breakdown of the cell membrane significantly enhances the entry of nanoparticles and their complexes to the body.
The amalgamation of amoxicillin with AgNPs markedly diminishes bacterial growth, whereas the AgNPs-ampicillin combination has superior effectiveness against Staphylococcus, Escherichia coli, and Klebsiella, as shown by previous studies. Indicates improved efficacy against P. aeruginosa in both in vitro and in vivo settings when gentamicin is encapsulated in poly (lactide-co-glycolide) (PLGA) nanoparticles; this feature is further highlighted when compared to the administration of amoxicillin alone [84]. The development of broad-spectrum bactericidal drugs that circumvent the resistance mechanisms of multidrug-resistant strains of P. aeruginosa, Enterobacter aerogenes, and Methicillin-resistant Staphylococcus aureus (MRSA) was made possible by the attachment of ampicillin to the surfaces of AuNPs and AgNPs [85]. Bimetallic nanoparticles in combination with core-shell linezolid shown strong bactericidal action against all tested organisms, including MRSA, whereas colistin demonstrated enhanced efficacy against antibiotic-resistant E. coli [86, 87] .
Metallic nanomaterial’s as antibacterial agents
Many hypotheses and studies suggest that nanoparticles (NPs) may change the shape and structure of microorganisms, rendering them incapable of survival. Sondi and Salopek-Sondi (2004) gave the example of NPs binding to bacterial cell walls or membranes, penetrating them, and causing cell death via structural abnormalities in membrane permeability [88]. Nanometers are the smallest unit of measurement for nanomaterials, attesting to their very microscopic size. Small in stature, they differ from bulk materials in a number of important physicochemical ways [89]. According to Lee et al. (2019), these traits govern their antibacterial effectiveness, drug transporter usefulness, and toxicity [90]. Nanoparticles, which may be anywhere from 1 to 100 nm in size, can interact with a wide variety of biomolecules inside cells, including DNA, proteins, and lipid membranes [91]. Bacterial DNA and cell membranes may be harmed by such interactions [92]. The researchers, Morones et al. (2005), have stated that silver nanoparticles (Ag NPs) in the size range of 1–100 nm possess stronger bactericidal properties towards gram-negative bacteria [93]. This is due to the fact that the NPs can be in close to intimate contact with the bacterial cells. The fact that they are little in height should enable them to overcome any biological challenge. In addition, their size might affect their pharmacokinetics [94]. One important feature of nanoparticles is their high surface-to-volume ratio, which increases their antibacterial activity. Free radical production, which increases as the surface-to-atomic bonding ratio grows, is what causes oxidative damage to bacteria [95]. The atom is more functional with a wide range of ligands and substances, including antibodies and medications, due to its enhanced surface area [96]. Nanoparticles’ surface charges may create a variety of electrostatic interactions that might affect biological systems [97]. Negatively charged cell membranes attract cationic nanoparticles, which may swiftly infiltrate bacterial cells, whereas anionic nanoparticles are rejected [98]. Nanoparticles that are cationic are more likely to damage DNA molecules that are negatively charged [99]. Additionally, nanoparticles have photothermal activity, electron transfer capacity, and hydrophobicity, which all support their effectiveness against microorganisms [97].
Silver nanoparticles
Silver nanoparticles (AgNPs) have one of the most well investigated examples of inorganic nanoparticles since it has a potent and extensive antimicrobial effect. They have antibacterial actions that are executed in a variety of ways, which include the release of Ag + ions, production of reactive oxygen species, and damage of bacterial cell membranes and DNA. Silver nanoparticles work with Gram-positive and Gram-negative bacteria including multidrug-resistant ones. Their high starting reactivity and making is advantageous to their use in antimicrobial coating, wound dressings, and medical devices [100].
A novel class of antibiotics may emerge from AgNPs and their potent antibacterial properties [101], asserted that of all commercially available nanoparticles, silver nanoparticles (AgNPs) are the most sought after. Because they are less harmful than other nanoparticles, research into their potential application as antibacterial agents has advanced quickly. According to Singh et al. (2015), the harmful mechanism of AgNPs frequently begins with adhesion and advances by infiltration into the bacterial cell membrane [102].
Metallic nanoparticles (NPs) are broad spectrum antimicrobials with multiple and simultaneous mechanisms of intervention overwhelming the bacterial defense measures. Following their interaction with the bacterial surface or the entry of NPs into the cell through porins, metal ions are released, which causes excessive production of reactive oxygen species (ROS), causing oxidative stress. This stress disrupts and causes cellular membranes through lipid peroxidation, the electron transport chain and proton motive force and protein misfolding and inhibition of enzymes. Moreover, ROS and metal ions cause direct DNA damage, replication, and transcription damage, and eventually death of bacterial cells. As a countermechanism to this, bacteria can use various resistance mechanisms including: efflux pumps, ROS-scavenging mechanisms, DNA repair mechanisms, nanoparticle immobilization and biotransformation, yet these responses tend to be ineffective against the combined toxicity of NPs as shown in Fig. 3.
Fig. 3.
Diagrammatic representation of the antimicrobial action of metallic nanoparticles A, and bacterial mechanism of resistance B. Nanoparticles cause damage of the membrane, ROS formation, dysfunction of proteins, enzyme inhibition and DNA damage resulting in oxidative stress and cell death. Bacteria overcome these effects by means of efflux, ROS scavenging, DNA repair, and nanoparticle immobilization or aggregation
Reactive oxygen species (ROS) and oxidative stress are produced when internal structures are compromised by the release of Ag+ ions [102, 103]. The sodium/potassium ion ATPase pump and a number of signal transduction pathways are consequently impacted. The combination of Ag+ ions and AgNPs with phosphorus-containing DNA may result in protein inactivation and bacterial cell death [104], found that interactions between oxygen, Sulphur, Chlorine, and Thiols may significantly affect the release of Ag+ ions. According to Sriram et al. (2012) [105] and Abuayyash et al. (2018) [106], the Ag + ion’s dimensions have a major impact on its emission rate.
Because of their small size, silver nanoparticles (AgNPs) may enter cells quickly. Besides inducing cell death, they modify the membrane’s structure and content, hence enhancing its permeability. The efficacy of AgNPs is contingent upon the specific bacterial species involved. This results from differences in the structure, thickness, and composition of the cell wall [107]. The distinctive antibacterial efficacy of AgNPs is associated with the generation of reactive oxygen species and the degradation of the cell wall and plasma membrane, as shown by [108]. The inactivation of proteins and lipid peroxidation inside their membranes further facilitates this process. These processes compromise the membrane’s structural integrity, hence disrupting the transport proteins and resulting in potassium leakage.
Gold nanoparticles (AuNps)
Gold nanoparticles (AuNPs) represent biocompatible nanomaterials that are extensively used in biomedical activities because of their chemical stability and surface functionalization. Even though their inherent antimicrobial effect is lower compared to that of silver nanoparticles, they can be very effective when they are conjugated with antibiotics, peptides, or other bioactive molecules. They increase the performance of antimicrobials by improving the efficiency of drug delivery, attacking bacterial cells, and disrupting bacterial biofilm. These characteristics increase the value of AuNPs as platforms for advanced antimicrobial and therapeutic uses [109].
The antibacterial properties of silver nanoparticles (AuNPs) have attracted considerable scholarly interest [110, 111]. Abdel-Raouf et al. (2017) assert that AuNPs may assume several geometries, including spherical, triangular, hexagonal, and rod-like shapes [112]. Smitha and Gopchandran (2013) found out that triangular-shaped AuNPs displayed better antibacterial properties in various microorganisms compared to the round shaped AuNPs. Electrostatic interaction between AuNPs and the membrane eliminates the integrity of the membrane [113]. They can break the membrane and snatch the constituents of the cell within the cell. The ability of gold nanoparticles (AuNPs) to bind to a DNA can inhibit DNA transcription and replication. Besides, they can be incorporated into the biofilm of bacteria. Also, in contact, the AuNPs generated reactive oxygen species (ROS), which is another way in which the particles killed cells. They change membrane potential and inhibit the activity of ATP synthase enzymes among other effects on bacterial metabolism. Like AgNPs, AuNPs can affect cell membrane stability and integrity [114]. According to Cui et al. (2012), AuNPs stop rRNA from binding to its subunit, which hinders protein translation. AuNPs can attach to nucleotides that contain phosphorus or sulphur. Antibiotics’ strong antibacterial efficacy is frequently increased when they are included in AuNPs [57]. Research by Brown et al. (2012) demonstrated the efficacy of ampicillin in combination with AuNPs against ampicillin-resistant E. coli, Enterobacter aerogenes, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa [80]. The AuNPs-AMP combination catalyzes the transmembrane pump while inhibiting and impairing drug efflux. The substantial amount of β-lactamase produced by bacteria is efficiently neutralized by the combination of AuNPs and AMP [115].
Nitric oxide-releasing nanoparticles (NONPs)
Nitric Oxide-Releasing Nanoparticles (NONPs) are engineered nanoparticles, lifeless nanomaterials engineered to benefit the controlled and sustained release of nitric oxide, which is a powerful antimicrobial and signaling molecule. They demonstrate the broad-spectrum antibacterial action based on causing nitrosative stress, which causes destruction of bacterial DNA, proteins, and membranes. The effectiveness of NONPs is especially evident in the case of biofilms and multidrug-resistant bacteria, and it can be ascribed to the multidimensional mechanism of action. Also, regulated NO release reduces the toxicity and increases the therapeutic effectiveness in biomedical practice [116].
Numerous susceptible and antibiotic-resistant bacteria, such as E. faecalis, E. coli, K. pneumoniae, S. pyogenes, and P. aeruginosa, have their growth significantly inhibited by nitric oxide (NO) releasing nanoparticles (NONPs). Hydrophilic, lipophilic, and oxygen-unstable are some of the characteristics of natural gas, or NO [117]. So, nitric oxide (NO) kills microbes and causes cell damage with its reactive nitrogen and oxygen species. They are byproducts of the reaction between nitric oxide and superoxide or oxygen. The synthesis of these intermediates becomes physiologically relevant at NO concentrations higher than 1 M. RNOS, such as peroxynitrite, nitrogen dioxide, iron-dinitrosyl complexes, and S-nitrosothiols (RSNO), are produced as a result of these concentrations as shown in Fig. 4 [117].
Fig. 4.
Schematic representation of the multifaceted antibacterial mechanisms of nanoparticles, including membrane disruption, intracellular penetration, oxidative stress via ROS generation, interference with protein synthesis and genetic processes, and inhibition of biofilm formation. These combined actions ultimately lead to cellular dysfunction and bacterial cell death
Rubbo et al. (1994) demonstrated that nitric oxide breaks down lipids using nitrogen dioxide and peroxynitrile [118]. When peroxynitrite causes lipid peroxidation in liposomes, nitric oxide’s antibacterial qualities are enhanced [119]. Among the inert chemical groups and residues present on proteins are reactive thiols, heme groups, aromatic or phenolic amino acids, amines, and tyrosyl residues [120]. Researchers have demonstrated that nitric oxide radicals can make aconitase, NADH dehydrogenase, and succinate dehydrogenase inactive in nitric oxide-induced cytotoxicity tests. This provides further evidence that nitric oxide radicals might cause an iron deficiency by directly liberating iron from metalloenzymes [121]. Nitrosating intermediates cause DNA damage when reactive nitrogen species (RNOS) autoxidate nitric oxide, which in turn causes the deamination of cytosine, adenine, and guanine. Nitrogen dioxide and peroxynitrile are the most effective DNA modifiers and breakers among these reactive nitrogen species (RNS). On the other hand, cysteine residues in DNA alkyltransferases may interact with NO to produce NO-S adducts since they contain -SH groups. This is due to the fact that these adducts stop the protein from obtaining the guanine alkyl group. Because NO inhibits the DNA repair enzymes’ ability to work on alkylated DNA, this kind of DNA cannot be repaired [122, 123]. Compared to human cells, prokaryotes are more dependent on iron-sulfur clusters, making them more amenable to nitric oxide therapy [124].
Consequently, NO-releasing nanoparticles could be a useful strategy for fighting bacterial species that exhibit drug resistance. Nitric oxide nanoparticles administered gradually over time were reported to suppress MRSA and Acinetobacter baumannii in wound and soft tissue models in mice [125, 126]. According to the research, NONP therapy has the potential to increase collagen formation, which in turn speeds up the healing process. NONPs may alter immune responses to reduce bacterial burden, according to the evidence. Friedman et al. looked into the effectiveness of NO-NPs against gram-positive and gram-negative bacteria in the lab. Among the microorganisms analysed were E. coli, P. aeruginosa, K. pneumoniae, S. pyogenes, and E. faecalis, which are significant for clinical treatment. Both bacterial species’ growth was significantly inhibited by the NONP dosage. While NO-NPs effectively stopped the growth of Gram-positive bacteria for 8 to 16 h at lower concentrations, they dramatically decreased the growth of Gram-negative bacteria within 24 h [127].
Nanoparticles of copper and its oxides
Copper nanoparticles of copper and its oxides, have been confirmed to have a significant antimicrobial effect, which is associated with the release of copper ions, the formation of reactive oxygen species, and membrane destruction. These nanoparticles affect the activity of fundamental bacterial enzymes and produce oxidative stress, which causes the effective inhibition of Gram-positive and Gram-negative bacteria. Copper nanoparticles are cheaper substitutes of noble metals and hold a potential over multidrug-resistant organisms. They are stable and exhibit a wide range of action and therefore can be used in antimicrobial coatings and biomedical utilization [128].
El-Batal et al. (2016) and Asemani and Anarjan (2019) have demonstrated the antibacterial capabilities of copper and its oxide nanoparticles (CuNPs or CuONPs) [129, 130]. The negative charge of nanoparticles (NPs) accounts for their antibacterial properties, as shown by the existing literature [131]. The Cu2 + ion can enter the cell by ignoring the lipid bilayer. Reactive oxygen species (ROS) are quickly released upon cell entrance. Lipid oxidation and protein oxidation are complimentary processes [132]. The antibacterial properties of copper become clear when its oxidation state changes from + 1 to + 2. CuONPs’ antibacterial activity may be greatly impacted when combined with amino acids, according to research [133].
Nanoparticles of zinc oxide (ZnONPs)
Zinc oxide nanoparticles (ZnONPs) have been extensively known to have high antimicrobial activity and biocompatibility. They accomplish the effects of anti-bacteria mainly by production of reactive oxygen species, blanketing Zn2+ and bacterial cell membrane destabilization. ZnONPs have a wide spectrum of action against pathogens, multidrug-resistant bacteria included, and they have the antibiofilm effect. These characteristics render them favorable in the use of antimicrobial coatings, wound healing, as well as biomedical devices. According to Bhuyan et al. (2015), zinc oxide nanoparticles are an excellent antimicrobial. A prior work revealed that the surface coating of ZnONPs could hinder their interaction with biological fluids [134]. Agglomeration is caused by PEGylated ZnONPs’ strong affinity for and interactions with lactic and citric acid. According to Pranjali et al. (2019), ZnONPs coated with PEG had a far lower bacterial inhibitory efficacy than those that weren’t. When ZnONPs come into contact with a bacterial cell, they damage the bacterial cell membrane and liberate zinc ions [135]. More cellular damage results from the interaction of zinc ions with several intracellular components [136]. Reactive oxygen species generation may be aided by zinc ions [137, 138]. According to a study, thiosemicarbazide and glutamic acid-functionalized ZnONPs influenced the expression of efflux pump genes in a variety of drug-resistant S. aureus strains [139].
Nanoparticles of titanium oxide (TiO2NPs)
Titanium dioxide nanoparticles (TiO2 NPs) can fight MDR bacteria by a mechanism involving the production of reactive oxygen species (ROS) in the presence of UV or visible light, which produce damage to bacterial cell walls, proteins, and DNA. Their large surface area accelerates bacterial membrane damage and biofilm prevention effects, and hence is used with drug-resistant strains. Moreover, TiO2 NPs may be used in the combination with antibiotics to enhance their effects and minimize the emergence of resistance. According to Singh et al. (2018), TiO2 nanoparticles cause oxidative phosphorylation disruption and cell membrane damage by generating reactive oxygen species (ROS). TiO2NPs not only obstruct the coenzyme-independent respiratory network and signalling pathways, but they also prevent iron and phosphorus from being absorbed and transported [140]. Foster et al. (2011) found that it also reduces the synthesis and degradation of heme groups [141]. Research has shown its ability to generate free radicals, in addition to being light-dependent [142]. Liu et al. (2010) demonstrate its capacity to disrupt peptidoglycans, lipopolysaccharides, and phospholipid bilayers [143].
Magnesium oxide nanoparticles (MgONPs)
Reactive oxygen species (ROS) generated by MgONPs have been proposed to cause serious cell damage [144, 145]. According to the authors Nguyen et al., magnesium oxide nanoparticles (MgONPs) destroy E. coli cells by rupturing their membranes and prevent S. epidermidis biofilm development. They may be able to inhibit bacterial growth by quorum sensing, ROS production, or the production of Ca2 + concentrations. According to Nguyen et al. (2018), when MgONPs stick to cell membranes, it weakens them and causes intracellular components to leak out. Nanoparticles of magnesium oxide and manganese oxide were synthesized using an extract from Matricariachamomilla L [146]. These results show that nanoparticles may enter cells and damage their membranes. This led to the release of cytoplasmic material from inside the cell, and studies have shown that MgONPs are efficient against bacteria because they generate Mg2 + ions, come into contact with the cell membrane, and cause changes in pH as shown in Table 1 [147].
Table 1.
Represents the class of nanoparticles and their mode of action in the target organism
| Nanoparticles (NPs) | Minimum concentration | Synthesis method | Mode of action | Target microorganisms | References |
|---|---|---|---|---|---|
| CuO NPs | 1–10 µg/mL | Chemical synthesis | ROS generation | Streptococcus mutans, Lacticaseibacilluscasei, Lactobacillus acidophilus | [148] |
| 100–1,000 µg/mL | ROS generation | Candida albicans, C. glabrata, C. krusei | [148] | ||
| Green-synthesised ZnO NPs | 0.025 mg/mL | Plant-mediated green synthesis | Breakdown of membranes and production of ROS | Escherichia coli, Staphylococcus aureus, Klebsiellapneumoniae, Enterococcus faecalis | [149] |
| Green-synthesised nano copper | – | E. coli, Proteus sp., Enterococcus sp., Klebsiella sp. | [150] | ||
| Green-synthesised AgNPs | 0.11–7.1 µg/mL | – | S. aureus, E. faecalis, P. aeruginosa, A. baumannii, E. coli | [151] | |
| Green-synthesised AgNPs | – | Biological green synthesis | – | Streptococcus pneumoniae, Klebsiellapneumoniae, Salmonella typhimurium | [152] |
| SPIONs (Superparamagnetic Iron Oxide NPs) | 20 µg/mL | Co-precipitation/physical synthesis | – | Pseudomonas aeruginosa, Candida albicans | [153] |
| AgNPs | 4–16 µg/mL | Chemical reduction | Scavenging of hydrogen peroxide | Escherichia coli, Enterococcus faecalis, Salmonella typhi | [154] |
| SeNPs | 82–660 µg/mL | Chemical / biological synthesis | Membrane breakdown and oxidative stress | Escherichia coli, Staphylococcus aureus | [155] |
| AuNPs/MOFs hybrid | – | Hybrid nanocomposite synthesis | Peroxidase-like activity; production of hydroxyl radicals (•OH) | Escherichia coli, Staphylococcus aureus | [156] |
| GO/AgNPs and GO/CuO NPs | – | Nanocomposite synthesis | production of ROS | Staphylococcus aureus, Escherichia coli | [157] |
| Zn₀.₉₅Ag₀.₀₅O (ZnAgO) NPs | – | Doped metal oxide synthesis | ROS production; rupture of the membrane | Staphylococcus aureus, Escherichia coli | [158] |
| ZnO NPs | 0.2–1.4 mM | FtsZ interference, membrane rupture, and electrostatic interaction | Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis | [159] | |
| Nickel oxide NPs | 20 µg/mL | Chemical synthesis | Ni2+ ion release; ROS generation | Escherichia coli (Gram-negative) | [160] |
| Antibiotic-loaded mesoporous silica NPs decorated with SPIONs | 200 µg/mL | Drug-loaded hybrid NPs | Magnetic hyperthermia under an alternating magnetic field | Escherichia coli biofilms | [161] |
| PVA/starch/chitosan films with NiO–CuO | 160–0.156 µg/mL | Polymer nanocomposite | ROS production and metal ion release | Escherichia coli, Staphylococcus aureus | [162] |
| TiO2 NPs | 1,000 µg/mL | Sol–gel/chemical synthesis | ROS generation | Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus | [163] |
| TiO2 nanorods | 10 mM | Nanorod chemical synthesis | Ag+ ion release; ROS production | Staphylococcus aureus | [164] |
Ferric oxide nanoparticles (Fe3O4NPs)
Ferric oxide nanoparticles (Fe3O4NPs) fight the AMR bacteria using both their magnetic and oxidative characteristics that interfere with bacterial cell walls and membranes. They are able to produce reactive oxygen species (ROS) that harm cell constituents as well as block biofilm formation. Moreover, Fe3O4 NPs may be additional carriers of the antibiotics to improve their delivery and overcome the resistance mechanisms. Studies suggest that ferric oxide nanoparticles may reduce H+-efflux across microbial cell membranes. Iron oxide, when administered as nanoparticles, significantly diminishes ATP-associated metabolism. Additionally, a decrease in membranes linked to H2 generation was found by [165]. The antibacterial effectiveness of iron oxide nanoparticles (Fe2O3 NPs) and biosynthesised iron nanoparticles (Fe NPs) has been extensively studied [166, 167]. The antibacterial qualities of calcium oxide nanoparticles have been the subject of several investigations [168, 169].
Dendrimers
Dendrimers are a family of highly branching, tree-like macromolecules with a variety of biological functions that may be categorized based on their basic structure and surface characteristics. Very high percentage (97.98%) An abundance of literature has focused on polyamidoamine (PAMAM) dendrimers for their drug-encapsulating and conjugating properties as well as their homogeneous structure [170, 171]. When compared to anionic or neutral PAMAM dendrimers, cationic and higher-generation PAMAM dendrimers exhibit greater levels of immunogenicity and cytotoxicity. Careful design is required to guarantee the safe medical use of PPI dendrimers, despite their bioactivity and broad variety of functionalization possibilities, because of the toxicity associated with their manufacture and terminal group chemistry. Because of their silicon-based backbones, over Carbosilane dendrimers are less immunogenic and toxic than cationic PAMAM dendrimers, making them more appropriate for use in biological applications [172]. Dendrimers of peptides are ideal for gene transfer and antimicrobial applications because they have been designed to have minimal immunological reactivity and biocompatibility while retaining a variety of capabilities. Antimicrobial medication delivery was one of the earliest uses of dendrimers as a pharmaceutical carrier [173]. Their capacity to target drug release and substantially load medicines against resistant bacteria has been demonstrated by early studies in this area. Dendrimers have several uses, including as membrane penetration and tailored drug administration, and their 125 surface functions largely define their bioactivity. Cytotoxicity and immunogenicity are reduced by dendrimers with neutral or anionic terminal groups; nonetheless, cationic dendrimers have the potential to induce cell death by electrostatic membrane disruption. Enumeration 97−10 Despite dendrimers’ promising future, they do have several drawbacks [174]. Some of these potential drawbacks include cytotoxicity (particularly in cationic forms), immunogenicity, decreasing permeability with generations, and difficult or costly purification and manufacturing processes. Biological dendrimers undergo a plethora of alterations to improve their efficiency and safety, such as surface neutralization, which decreases immunogenicity, and PEGylation, which promotes solubility and circulation [175, 176]. Thorough evaluation of dendrimers’ classification, synthesis, and functionalization is necessary to achieve our goals of making them more consistent for diagnostic or therapeutic usage, with fewer side effects, and more biocompatibility [174].
Some presently insoluble drugs may be able to be made more bioavailable and soluble by dendrimer synthesis. Such particles may respond to environmental cues, such as pH levels and enzyme concentrations, allowing for targeted delivery and the potential treatment of diseases resistant to conventional medicine [177]. The Table 2 represents different types of nanoparticles and their mechanism of action.
Table 2.
represents the multi-drugs bacteria and use of nanoparticles for their killing along with mechanism of action
| Type of nanoparticles | Targeted bacteria | Antibiotic resistance type | Mechanisms of antibacterial action | References |
|---|---|---|---|---|
| AgNPs | Enterococcus faecalis, S. aureus | Vancomycin-resistant | Vancomycin and the synergistic effect that results in cell death | [178, 179] |
| Enterococcus spp. | – | Ongoing investigations | [180] | |
| S. aureus | Methicillin-resistant | Physical adherence to bacterial cells and antibiotic synergy | [80, 181] | |
| E. coli, P. aeruginosa | Ampicillin-resistant | Synergy with ampicillin, enabling cell entry; inhibition of cell wall, protein, and nucleic acid synthesis | [80] | |
| Enterobacter cloacae, S. mutans | – | Membrane breakdown caused by ROS | [182] | |
| S. epidermidis, S. aureus | – | Biofilm penetration aided by magnetic fields | [183] | |
| E. coli | MDR | ROS generation | [184] | |
| E. coli, P. aeruginosa | – | – | [185] | |
| S. aureus, Enterococcus spp., P. aeruginosa, A. baumannii, Enterobacteriaceae | – | Interaction with biological components affecting chemical and physical qualities | [186] | |
| E. coli | – | – | [187] | |
| S. aureus, E. coli, P. aeruginosa, K. pneumoniae, B. subtilis | – | Bacterial cell wall penetration | [188] | |
| P. aeruginosa | – | Blue light-based synergistic treatment | [189] | |
| E. coli, P. fluorescens, P. putida, P. aeruginosa, B. subtilis, S. aureus | – | disruption of the cell wall | [190] | |
| A. baumannii | – | Membrane permeability modification | [191] | |
| Multiple species | – | – | [192, 193] | |
| E. faecalis | – | – | [194] | |
| S. aureus | MRSA | ROS and photothermal death | [195] | |
| E. coli, K. pneumoniae | Cefotaxime-resistant | DNA damage and disintegration of cell walls | [196] | |
| S. aureus, E. coli, P. aeruginosa, E. aerogenes | Ampicillin-resistant | Combining ampicillin to facilitate cell entrance | [80] | |
| Multiple species | Kanamycin-resistant | disruption of the cell wall | [197] | |
| Multiple MDR | – | ROS production, membrane disruption, and photothermal/photodynamic treatments | [198] | |
| zZnONPs | K. pneumoniae | Ampicillin/carbenicillin-resistant | ROS production and rupture of membranes | [199] |
| S. aureus | MRSA | Inhibition of enzymes | [200] | |
| E. coli | MDR | ROS-mediated membrane disruption | [201] | |
| S. aureus, P. aeruginosa | Biofilm | production of ROS | [202] | |
| CuO NPs/CuNPs | E. coli, S. aureus | MDR | ROS production | [203] |
| S. aureus | MRSA | Cu2+-DNA binding leading to helical disruption | [204] | |
| P. aeruginosa | Biofilm | penetration of cell walls and damage to nucleic acids | [205] | |
| Fe₃O₄ NPs | E. coli | MDR | RF-induced disruption of the membrane | [206] |
| S. aureus, P. aeruginosa, E. coli | – | Membrane penetration; electron transfer interference | [207] | |
| Al2O₃ NPs | S. aureus | MRSA | breakdown of cell walls and production of ROS | [208] |
| E. coli | MDR | Intracellular accumulation | [208] | |
| TiO2 NPs | S. aureus | MRSA | Thiol protein binding and ion release | [209] |
| E. coli | MDR | ROS and rupture of membranes | [201] | |
| Bimetallic NPs | S. aureus | MRSA | DNA damage, disruption of membranes, and suppression of protein synthesis | [141] |
| Au/Ag NPs | Enterococcus spp. | Vancomycin-resistant | Antimicrobial PDT plus SERS | [210] |
| Multiple biofilm-forming bacteria | – | Disruption of cell walls and inactivation of enzymes | [211] | |
| Cu/Ni NPs | S. aureus, E. coli, S. mutans | MDR | ATP increases ion adsorption | [212] |
| Graphene Oxide NPs | S. aureus | MRSA | Antibiotic combination + NIR exposure | [213] |
| GO NPs | E. coli, E. faecalis | MDR | UV-driven ROS | [214] |
| SeNPs | S. aureus, E. coli | MDR | Cell wall disruption; targeted treatment | [215] |
| S. aureus | MRSA | NIR-directed photothermal treatment | [216] |
Carbon-based nanostructures
Graphene quantum dots (GQDs), fullerenes, carbon nanotubes (CNTs), graphene oxide (GO), reduced graphene oxide (rGO), carbon nanofibers, and carbon dots (CDs) are among the numerous carbon-based nanostructures with biological applications and antibacterial properties. Materials such as graphene, graphene oxide (GO), and carbon nanotubes (CNTs) can be produced using both top-down (by chemical synthesis or vapor deposition) and bottom-up (via exfoliation of graphite) methods [217, 218]. According to research, carbon-based nanomaterials like graphene oxide and carbon nanotubes have the potential to enhance physical and chemical functionalization, targeting capability, drug loading, and dispensability through the disruption of microbial membranes and the generation of oxidative stress [219]. These techniques include heteroatom doping, bio-conjugation, noncovalent interactions, and covalent attachment of functional groups. The immunogenicity and cytotoxicity profiles of carbon-based nanostructures are significantly influenced by three key factors: surface chemistry, particle size, and the amount or kind of functionalization [220, 221]. According to recent research, functionalization usually promotes biocompatibility, decreases immunogenicity, and permits bioactivity customization. Aggregation, sharp edges (like GO sheets), and leftover catalysts that might cause cytotoxicity or immunological activation are significant drawbacks in various biological contexts [222, 223].
There are many different antimicrobial mechanisms that have been found. When carbon nanotubes (CNTs), graphene oxide (GO), or fullerenes get into close proximity to the bacterial cell wall, they may hinder metabolism and cause cell death. The processes include an overabundance of reactive oxygen species (ROS), interference with energy metabolism or DNA activity, and mechanical membrane rupture (especially for two-dimensional structures like GO) [217]. The antibacterial capabilities of carbon nanostructures are highly reliant on their size and surface charge. Because they have a higher surface area to volume ratio, particles with smaller volumes are better at interacting with bacteria. The likelihood of membrane rupture is increased because surfaces with a positive charge may cling firmly to negatively charged bacterial membranes. According to the research, smaller carbon dots are more effective against germs. This is due to their enhanced membrane contact and increased ability to produce reactive oxygen species (ROS) [218]. It is possible to build antibacterial mechanisms using a variety of carbon-based nanoplatforms. Fullerenes and graphene oxide (GO) function through membrane slicing and oxidative stress; carbon dots and photo-induced processes; virgin or functionalized carbon nanotubes and nanodots; and hybrid composites mostly through ROS generation and metabolic disruption [224].
The immunologic profile, therapeutic use, and antibacterial activity of carbon nanomaterials are influenced by a variety of factors, including the kind of nanomaterial, its size, surface charge, functionalization, and hybridization. numbers on pages Today, a wide range of GO nanostructures are available, such as nanosheets, quantum dots, nanoribbons, and hybrid composites that combine GO with other materials, such GO decorated with metal nanoparticles or embedded in polymeric matrices [225].
Synthesis procedures that establish the physical and chemical properties of each structure include chemical exfoliation, Hummers’ method, and electrochemical techniques, among others. Each of these features, layer count, lateral dimension, oxidation level, and defect density, influences the antimicrobial effectiveness. Metals (e.g., silver, nickel, copper), polymers, and proteins may all be conjugated with GO nanostructures, and non-covalent adsorption and covalent grafting are further options for further functionalization. They lose their dispensability and biological interaction properties as a result of this alteration. 160,000 to 122,000 [226]. The intrinsic size and compositional variety of GO nanostructures, the risk of aggregation, the challenges in managing toxicity, and the issues with dependable large-scale production are some of the downsides of employing these structures (16%), (14%), 12%, (14%) [227]. GO’s size (smaller sheets may damage membranes and increase oxidative stress), surface charge (usually negative but variable), and oxidation level are some of its fundamental properties. Bacteria are physically trapped by larger sheets. Physical piercing of bacterial membranes by medicines and sheets with sharp edges and a high defect density allows for bactericidal or bacteriostatic wrapping or entrapment. (16%), (14%), 12%, (14%). Incorporating additional materials like AgNPs, copper nanoparticles, and nickel colloidal clusters into GO nanoplatforms may enhance their effectiveness against bacteria and other resistant microorganisms. These nanoplatforms may release metal ions from the composite, trap and disturb metabolism, or break membranes with sharp nanosheets; the exact mechanism by which they do these things depends on the specific GO-based nanostructure. While functionalization with AgNPs enhances bactericidal activity through physical and chemical mechanisms, hybridization with biomolecules or polymers may reduce cytotoxicity and improve biocompatibility [228, 229].
Graphene oxide has shown promise in the battle against Klebsiella and methicillin-resistant Staphylococcus aureus, according to the research. Its synergistic effects when combined with antibiotics and other nanoparticles make it useful in nanocomposites production. Drug administration, wound dressings, and biofilm removal are just a few of the many uses made possible by its biocompatibility and water dispersibility [230–232].
CNTs nanostructures
There are multiple CNT nanostructures, each with distinct structural traits and manufacturing processes. Carbon nanotubes with single walls (SWCNTs), multiple walls (MWCNTs), and double walls (DWCNTs) are a few examples. Geographical Multi-walled carbon nanotubes (MWCNTs) include several concentric graphene cylinders and are often manufactured using Gas-phase deposition, Laser irradiation removal, or arc evaporation, in contrast to single-walled carbon nanotubes (SWCNTs), which are frequently produced using other techniques. Improving the effectiveness of carbon nanotubes (CNTs) may be accomplished by covalently bonding proteins, polymers, or pharmaceuticals to their surface. This promotes increased antibacterial effectiveness, higher solubility, better dispersion, and reduced cytotoxicity [233, 234]. The needle-shaped CNTs exhibit enhanced electrical conductance and structural strength, enabling them to infiltrate bacterial cell membranes and induce cell death by the release of cytoplasmic contents. Carbon-based nanomaterials, whether single-tube or multi-tube structures, may demonstrate antibacterial properties when combined with different metal ions [235, 236]. This would establish them as a potential antibiotic delivery system capable of bypassing efflux pumps. They provide essential support for biosensors and enable drug administration. Carbon nanotubes has the capacity to penetrate cell membranes, possibly interfering with several biological activities [237]. The surface chemistry, physical characteristics, and degree of functionalization of carbon nanotubes are directly related to their immunogenicity and bioactivity [238]. In contrast to virgin carbon nanotubes (CNTs), which may provoke cytotoxicity and inflammatory responses despite their significant bioactivity, functionalized CNTs, particularly those modified with carboxyl or amino groups, often exhibit less toxicity and improved biocompatibility common negative outcomes include edema, oxidative stress, aggregation in biological environments, and heterogeneity across batches due to changes in surface characteristics and synthesis techniques [239, 240].
Nanoparticle clinical trials in MDR bacteria
Nanoparticles: Nanoparticles are developing as an emerging approach in initial clinical intervention of infection by MDR bacteria, whereby standard antibiotics are ineffective. It is observed that the clinical environment is at present now characterized by early phase trials and exploratory research as opposed to the late phase efficacy trials, which highlights the potential of nanomedicine in infectious diseases, as well as the developmental challenges thereof. Indicatively, a Phase 1 trial in Egypt compared the injection of PLGA nanoparticles loaded with ciprofloxacin against endodontic infections of antibiotic-resistant Enterococcus faecalis, and showed controlled and extended delivery of drug, potentially useful in the treatment of biofilm-mediated resistance in dental tissue (NCT05442736).
Likewise, nanosilver fluoride has undergone clinical trials in Brazil on caries prevention with the capability to diminish Streptococcus mutans biofilm, which is evidence of non-toxic and active anti-microbial utilization of silver nanoparticles (AgNPs) within the mouth (NCT01950546). These studies mainly determine safety and initial efficacy, which strengthens the translational importance of nanoparticles as carriers of antimicrobial agents and direct agents against antimicrobial resistance in pathogens [241]. Among nanoparticles of metals, AgNPs are the most studied in both preclinical and clinical settings since they have inherent antimicrobial properties and are a wide-spectrum nanoparticle [242]. Several in vitro experiments have verified that AgNPs could interfere with bacterial membranes, cause excessive production of reactive oxygen species (ROS), and interfere with virulence factor expression by the resistant strains, such as multidrug-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae, and could inhibit biofilm formation and increase their vulnerability to antibiotics [241]. AgNPs exhibited minimum inhibitory concentrations (MICs) in the low microgram range and had a substantial inhibitory effect on biofilm production and motility in clinical isolates of MDR and XDR P. aeruginosa, which also had demonstrated a potent additive effect with conventional antibiotic action.
Besides the antimicrobial effects, the nanoparticles are also being exploited in synergizing measures with the current methods to enhance them. According to clinical trials and laboratory researches, the results of combining the use of metallic nanoparticles and the orthodox antimicrobial agents are much better than when using drugs alone. Quite a striking preclinical demonstration was that of green-synthesized silver nanoparticles (Silver nanoparticles-colistin) that declined biofilm formation by carbapenem resistant P. aeruginosa, as well as down-regulation of quorum sensing genes, which mediate virulence and resistance, implying that nanoparticle adjuncts can enhance last-line antibiotics [243]. Nano-enabled testing enables The clinical trials of nanoparticle are listed in Table 3.
Table 3.
Represented the clinical trials of nanoparticles various region of world
| Nanoparticle type | Country | Target bacteria/Disease | Condition | Intervention | Outcome measures | Status/Phase | Reference/NCT No. |
|---|---|---|---|---|---|---|---|
| PLGA nanoparticles | Egypt | Enterococcus faecalis (Endodontic infections) | Antibiotic-resistant infection | Ciprofloxacin | controlled and prolonged medication release linked to infection prevention | Completed, Early Phase 1 | NCT05442736* |
| Silver nanoparticles (AgNPs) | Brazil | Streptococcus mutans (Dental biofilms) | Dental caries | Fluoride / Nanosilver fluoride | Assessment of the efficacy of nanosilver fluoride in preventing bacterial development in dental biofilm | Completed, Phase 1 | NCT01950546* |
| Au–Ag–Cu2Onanoshell hydrogel | China | Drug-resistant microbial keratitis | Ulcerative keratitis; microbial antibiotic resistance; photothermal therapy | Nanoshell hydrogel + voriconazole eye drops | Visual acuity evaluation (1 week, 1 month); contact tonometry (1 day, 1 week, 1 month | Unknown status, Early Phase 1 | NCT05268718* |
| Nanoparticles containing Glutathione | United States | Mycobacterial infection | Mycobacterium infection | Glutaryl solution vs. placebo | Reduced ROS and changed immune mediator profiles are linked to higher GSH levels. | Completed, Phase 1 | [244] |
Their antibacterial activity is significantly affected by their inherent physicochemical features, including diameter, surface charge, and length. Smaller SWCNTs, with a larger surface area, are anticipated to have superior antibacterial characteristics due to their capacity to infiltrate bacterial envelope and cause the efflux of internal cellular components. This results from their increased tendency to engage with and destroy bacterial cell envelopes. 0.13 of 127 was The length of carbon nanotubes (CNTs) influences their toxicological effects. Shorter tubes show increased open-end density, hence enhancing their antibacterial characteristics, while longer tubes are often less harmful to bacteria [239]. The surface charge affects antibacterial activity by diminishing membrane potential, augmenting cell adhesion, and modulating electrostatic interactions with negatively charged bacterial membranes. 0.13 of 127 was Carbon nanotube (CNT) nanoplatforms may be manufactured from many materials, including drug-conjugated CNTs, CNTs functionalized with metal oxides, polymer-CNT composites, and pure CNTs. These platforms function by physically breaking membranes, producing reactive oxygen species (ROS), encapsulating and surrounding microorganisms, and blocking metabolic processes. Metallic carbon nanotubes often have superior antibacterial activity compared to their semiconducting equivalents, attributable to differences in electron transport and the production of reactive oxygen species. The antibiotic impact may be further amplified by light activation, which increases ROS generation in bacterial cells [245]. The range, efficacy, and safety profile of CNT-based antibacterial nanostructures are all influenced by four variables: CNT type, synthesis and functionalisation, physicochemical characteristics, and the chosen platform material [246].
Fullerenes
Functionalized fullerols (hydroxylated fullerenes) and amino fullerenes are two examples of fullerene varieties. Endohedral fullerenes include metal atoms or clusters into their structure, while the more prevalent C60 (buckminsterfullerene) and C70 fullerenes are still others. Arc discharge, chemical vapor deposition, and laser ablation are three of the most frequent ways to make fullerenes. Their bioactivity, solubility, and the capacity to incorporate certain ligands may be altered, among other things, by adding amino, carboxyl, or hydroxyl groups [247]. Functionalization alters their biological interactions, hydrophobicity, immunogenicity, and biocompatibility, which in turn alters their antibacterial and cytotoxic activities. There are several restrictions on the biological use of fullerenes and their derivatives in the 135–137 nm region. For example, whether a drug causes cytotoxicity or inflammation depends on aggregation, surface chemistry, and dose [248]. A particle’s antibacterial activity is strongly affected by its size and surface. Components. The larger surface areas of tiny fullerenes make them more effective bactericides because they can adsorb onto bacterial membranes and penetrate bacterial cells more easily. Cationic fullerene derivatives have significant electrostatic interactions with Gram-negative bacteria, leading to the disintegration and ultimate death of bacterial cell membranes. The surface of Gram-negative bacteria’s cells has a net negative charge. The same logic applies to the ineffectiveness of anionic or neutral fullerenes [249, 250]. The design and functioning of nanoplatforms constructed from fullerene also vary. It does this by releasing ROS into the air. It was also shown that the fullerene C60 nanostructures have light-induced and antioxidant functions. When illuminated, their complicated, wriggly structure captures oxygen molecules, which then release reactive oxygen species. Together with antibiotics, they make it possible to administer medication more precisely while simultaneously killing germs via oxidative stress. A wide variety of bacteria, including drug-resistant strains, may be more effectively targeted by photodynamic methods using derivatives of hydrophilic or peptide-attached fullerene, which increase membrane contact and boost production of reactive oxygen species. Fullerene nanoparticles are superior antibacterial agents regardless of their molecular bonding state (cationic, amphiphilic, or metal-coordinated). Among these features is a decrease in bacterial energy metabolism and an enhancement of medicine penetration. The incorporation of fullerenes onto nanoplatforms made of metals, peptides, and polymers has the potential to increase the coverage of pathogens and the synergistic antibacterial effects [251–254].
Complications with the widespread use of antibacterial nanoparticles
Mondol et al. (2024) highlighted possible problems with price, sustainability, and industrial scalability [255]. There are still more obstacles to address, even with smart NPs that can respond to changes in light, pH, or bacterial enzymes [256]. Unresolved questions about cytotoxicity, oxidative stress, and potential environmental accumulation over the long term have limited their practical applicability. Xuan et al. (2023) and Wang YL et al. (2024) identified several promising advances in areas such as peptide-loaded systems, hybrid nanoantibiotics, and CRISPR-based carriers. However, these developments face significant difficulties, including inconsistent manufacturing., high costs, limited scalability, and a lack of regulatory support. The primary goal of scientific research should be the creation of biodegradable nanomaterials that do not harm living things [257, 258]. Extensive safety testing, AI-directed design, and publicly backed legislation are necessary for these technologies to reach the actual world (Olawade et al. [259] and Yan et al. [260], For NPs to be used safely in biomedicine while minimizing any possible side effects, their biocompatibility is of the utmost importance. Their therapeutic potential and side effects may be improved with careful design and surface modification [258].
Why nanobiotics matter
Nanobiotics, antimicrobial systems made up of nanoparticles, are recommended as a new generation or supplementary alternative to antimicrobials in addressing AMR. Compared to the conventional antibiotics, nanobiotics tend to have multimodal effects of action, such as membrane disruption, the production of reactive oxygen species (ROS), the release of metal ions, enzyme inhibition, and disruption of intracellular processes. The complex nature of this activity minimizes the chances of bacteria becoming resistant and allows taking effective measures against the MDR pathogens and biofilms [261]. Moreover, nanobiotics can be used as advanced drug-delivery systems through which the solubility, stability, and bioavailability of the current antibiotics can be enhanced. Polymeric and hybrid nanoparticles permit controlled and targeted release of drugs, increased concentrations of drugs in the local area and limited systemic exposure. The nanobiotics will be a strong approach to prolonging the clinical duration of the available antimicrobial drugs as well as meeting therapeutic gaps by providing improved antimicrobial efficacy and maintaining sensitivity in multidrug-resistant strains [262].
Advantages versus limitations of nanobiotics
Among the significant benefits of nanobiotics, the ability to act broad spectrum and synergistic against bacteria, fungi, and biofilms may be mentioned. Their adjustable physicochemical characteristics like size, shape, surface charge and functionalization, allow a specific interaction with the microbial cells. Moreover, the green-synthesized nanobiotics have enhanced bio-compatibility and sustainability and the hybrid and stimulus-sensitive systems (ex. photothermal or magnetic nanoparticles) offer new therapeutic opportunities of localized and resistant infections [263].
As much as these are the benefits, nanobiotics also have significant constraints. They can be very sensitive to environmental factors like pH and ionic strength and biological matrices affecting their antimicrobial activity and thus their performance can vary. Normalisation, rediscovery and permanence is still a problem, especially in the case of bioengineered nanoparticles. In addition to it, the absence of standardized testing systems complicates the direct comparison of nanobiotics across researchers, slowing its transition into clinical use [264].
Toxicity concerns
Toxicity has been one of the focal issues when developing nanobiotics because nanoparticles may not only seem to interact with the microbial cells but also with the host tissues. At high concentrations or with longer exposure, metal and metal oxide nanoparticles are also likely to cause oxidative stress, inflammation, mitochondrial dysfunction, and DNA damage in mammalian cells. The buildup of organs like liver, kidney, and spleen also increases the issue of safety in the long run. No full-scale toxicological data have been developed though strategies of green synthesis and surface functionalization have been demonstrated to reduce cytotoxicity. The majority of the available studies are based on in vitro or small-animal models of short term which may not be reflective of human responses. Consequently, before the use of nanobiotics in clinical practice can be taken up by a large number, it is necessary to carefully conduct systematic assessment of dose-dependent toxicity, biodistribution, metabolism, and clearance [265, 266].
Regulatory and translational barriers
There are influential regulatory challenges associated with translating nanobiotics, as a laboratory research, to clinical application. Existing governing structures were basically meant to be used when dealing with conventional small-molecule drugs and are not usually sufficient to regulate the complexity and variability of nanomaterials. Problems of characterization, consistency across batch-to-batch, consistency, and mechanism-based classification make the process of regulatory approvals more issue-convoluted [267]. Also, commercial and clinical translation is impeded by the high expenses of mass production, scanty evidence available on clinical trials and doubts about the safety in the long term. The lack of unified international standards on nanomedicine assessment further delays the approval and market entrance. These barriers will only be overcome after the concerted efforts of researchers, clinicians, industry, and regulatory agencies establish uniform protocols, strong safety tests, and a clear route of nanobiotic development [268].
Future perspectives
The proliferation of MDR bacteria and other pathogens has led to an increased use of antibacterial nanoparticles. Future study should aim to improve the biocompatibility, specificity, and environmental compatibility of these nanoparticles while minimizing their toxicity [269]. NPs need to be triggered by certain stimuli, such as bacterial enzymes, pH changes, or environmental factors like light and magnetic fields, in order to be effective antimicrobial agents. Multiple studies validate the concept that target-specific nanoparticles may reduce adverse effects. Copper sulfide (CuS) nanoparticles used in photodynamic therapy (PDT) and photothermal therapy (PTT) to enhance wound healing and demonstrate antibacterial capabilities represent a significant instance [270]. Likewise, nanocomposite hydrogels containing Lignin-containing hotoactive nanocomposites may eliminate microbial cells upon light exposurevia a pH-responsive controlled release mechanism. Alternatively, microbubbles including Fe3O4 nanoparticles use a magnetism-targeted approach [271]. According to Quiñones-Vico et al. [272], Pisani et al. [273], and Costabile et al. [274], the incorporation of nanoparticles with antibiotics is a significant breakthrough that enhances therapeutic potential. Abdullah et al. (2024) demonstrate that antibiotic-infused metal nanoparticles have potential efficacy against microbial resistance. Another issue for the future is improving the effectiveness of hybrid nano-antibiotic systems for all parties involved [275]. Ibraheem et al. (2022) found that polymeric nanoparticle-encapsulated antibiotics had enhanced bioavailability and decreased dosage needs owing to prolonged release and efficient penetration [276]. AgNPs’ advantageous carrier properties make them a suitable delivery system for biological drugs. When combined with ciprofloxacin, chemically reduced AgNPs exhibited increased antibacterial activity, and when loaded with vancomycin, the results were significantly better, according to Ibraheem et al. [276] and Veriato et al. [277].
For instance, nanoparticles encased in cell membranes or integrated with antimicrobial peptides may enhance targeting efficacy by mimicking a natural defensive response. Nanoparticles (NPs) incorporated with antimicrobial peptides or encapsulated in cell membranes may enhance targeted efficacy by mimicking the body’s intrinsic defensive mechanisms. Nanoparticles’ distinct physicochemical characteristics may prevent or delay the pharmaceutical’s breakdown within their encapsulation [278, 279]. Research revealed that the mean diameter of Chitosan-based nanostructures containing Synthetic LL37 antimicrobial peptide was 127.12 nm, with an encapsulation effectiveness of around 78% [280]. This combination of qualities produced strong antibacterial activity and increased stability. With minimum inhibitory concentrations (MIC) of 6 µg/mL, 23 µg/mL, and 31 µg/mL, respectively [156]. Similarly showed that the formulation of Nal-P-113-PEG-CSNPs (Nal-P-113 loaded PEG-Chitosan nanoparticles) inhibited the growth of Streptococcus gordonii, Porphyromonas gingivalis, and Fusobacterium nucleatum.
Conclusion
Nanomedicine has the potential to substantially improve the fight against multidrug-resistant diseases by enabling targeted intervention in afflicted areas, addressing biofilms, and reducing severe adverse effects. The use of antibiotics for both therapy and diagnosis is advancing the advent of diagnostic-therapeutic systems in pathogen-related illnesses. However, problems associated with safety, progress and regulatory compliance continue to exist. To progress, these difficulties need thorough examination, uniform techniques, and multidisciplinary cooperation. The amalgamation of nanotechnology, artificial intelligence, precision medicine, and CRISPR technology has considerable potential for the enhancement of antibacterial techniques in the future. Augmented funding for research, advantageous governmental rules, and partnerships between public and private sectors would bolster Nano medicine’s capacity to combat antibiotic resistance and guide methods for controlling infectious diseases.
Acknowledgements
The authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through Large Research Project under grant number RGP2/497/46.
Author contributions
A. Z. and S. Z. B. did the writing, manuscript, and analysis, while N. A. did data curation. M.Y.S. and A.M.A handled the conceptualization and writing editing of the manuscript.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Human and animal rights
This research does not include any human or animal subjects.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Akmal Zubair, Email: akmalkhattak1994@gmail.com.
Naila Afghan, Email: nailaafghan650@gmail.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.