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. 2024 Mar 11;17(3):e14430. doi: 10.1111/1751-7915.14430

The antibiotic crisis: On the search for novel antibiotics and resistance mechanisms

Marc W Van Goethem 1, Ramona Marasco 1,✉, Pei‐Ying Hong 1,2, Daniele Daffonchio 1
PMCID: PMC10926060  PMID: 38465465

Abstract

In the relentless battle for human health, the proliferation of antibiotic‐resistant bacteria has emerged as an impending catastrophe of unprecedented magnitude, potentially driving humanity towards the brink of an unparalleled healthcare crisis. The unyielding advance of antibiotic resistance looms as the foremost threat of the 21st century in clinical, agricultural and environmental arenas. Antibiotic resistance is projected to be the genesis of the next global pandemic, with grim estimations of tens of millions of lives lost annually by 2050. Amidst this impending calamity, our capacity to unearth novel antibiotics has languished, with the past four decades marred by a disheartening ‘antibiotic discovery void’. With nearly 80% of our current antibiotics originating from natural or semi‐synthetic sources, our responsibility is to cast our investigative nets into uncharted ecological niches teeming with microbial strife, the so‐called ‘microbial oases of interactions’. Within these oases of interactions, where microorganisms intensively compete for space and nutrients, a dynamic and ever‐evolving microbial ‘arms race’ is constantly in place. Such a continuous cycle of adaptation and counter‐adaptation is a fundamental aspect of microbial ecology and evolution, as well as the secrets to unique, undiscovered antibiotics, our last bastion against the relentless tide of resistance. In this context, it is imperative to invest in research to explore the competitive realms, like the plant rhizosphere, biological soil crusts, deep sea hydrothermal vents, marine snow and the most modern plastisphere, in which competitive interactions are at the base of the microorganisms' struggle for survival and dominance in their ecosystems: identify novel antibiotic by targeting microbial oases of interactions could represent a ‘missing piece of the puzzle’ in our fight against antibiotic resistance.

The looming threat of antibiotic‐resistant bacteria is one of the major challenges of the 21st century across clinical, agricultural, and environmental domains. Despite this crisis, the antibiotic discovery has stagnated, emphasizing the urgent need to explore yet overlooked ecological niches teeming with microbial competition. For istance, by targeting ‘microbial oases of interaction’, such as the plant rhizosphere, biological soil crust, deep‐sea and the more recent plastisphere, there is potential to uncover novel antibiotics. This approach represents a critical aspect of microbial ecology and evolution, offering a promising avenue in the battle against antibiotic resistance.

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BACKGROUND

The emergence of multiple antibiotic‐resistant bacteria in clinical, agricultural and environmental settings is arguably the foremost issue facing human health in the 21st century. The dissemination and evolution of novel antibiotic‐resistant bacteria have been described as the next global pandemic after COVID‐19, potentially leading to ~10 million human deaths per annum by 2050 (de Kraker et al., 2016). Critically, bacteria continue to evolve mechanisms to overcome our last resort antibiotics such as colistin, meropenem and vancomycin (Ferranti et al., 2018) and, despite recent promising breakthroughs in antimicrobial peptide discovery and the application of artificial intelligence (AI) for novel chemotype screening (Liu et al., 2023), our capacity to identify novel antibiotics has dwindled dramatically in the so‐called ‘antibiotic discovery void’. There is an urgent need to uncover novel antibiotic chemistries, such as the recently described indole‐2‐carboxylates (Brem et al., 2022) and other antimicrobial agents, preferably with high efficacies against multidrug‐resistant bacteria.

Given that approximately 80% of antibiotics used to combat infections are derived from natural or semi‐synthetic sources, we advocate that much effort towards novel antibiotic discovery could focus on ‘microbial oases of interactions’, particularly in highly competitive microbiomes within extreme or even novel ecological niches not yet explored, where (i) microbial interactions are prominent and (ii) microorganisms compete to ensure the limited space and resources available. These include the plant rhizosphere, biological soil crusts, hydrothermal vents, melting glaciers or even the most recently described plastisphere, among many others. By adopting the Darwinian idea of ‘the survival of the fittest’ to the microbial world, we anticipate that microorganisms – to ensure the effective colonization of such competitive niches – likely encode unique, specialized metabolites, possibly including as‐yet‐undiscovered antibiotics, which are crucial in their continuous adaption and counter‐adaption (competition) to each other's strategies (Granato et al., 2019). This ever‐evolving microbial ‘arms race’ is a fundamental aspect of microbial ecology and evolution, with significant implications for the diversity and structure of microbial communities, their resilience and stability (Ghoul & Mitri, 2016). The metaphorical ‘arms race’ reflects the constant struggle for survival and dominance in microbial ecosystems, as well as our fight against antibiotic‐resistant bacteria and its practical implications, particularly in the fields of medicine and biotechnology.

WHY DO MICROORGANISMS PRODUCE ANTIBIOTICS AND DEVELOP ANTIBIOTIC RESISTANCE?

Microorganisms, primarily bacteria and fungi, evolved diverse ‘weapon’ systems to harm and kill their competitors, including antibiotics, toxic proteins, viruses and more (Granato et al., 2019). Here, we broadly defined any antibacterial, antimicrobial or antifungal compounds – ranging from simple chemicals to complex peptides (Ciulla & Gelain, 2023) – as ‘antibiotics’. It is important to note that antibiotic production is not exclusive to pathogenic microorganisms; it is widespread among various environmental bacteria as well. These compounds have far‐reaching effects beyond their targeted antimicrobial actions, significantly impacting a broad spectrum of microorganisms. In this way, they influence the intricate microbial balance within ecosystems by shaping the composition, function and resilience of the communities (Ghoul & Mitri, 2016; Granato et al., 2019).

The production of antibiotics is a dynamic and evolving phenomenon shaped by the complex intra‐ and interspecies interactions among microorganisms, as well as by their environment. For instance, if we consider niches with nutrient and space limitations (i.e., stressful conditions), such as those developed in oligotrophic environments, antibiotic production allows bacteria to gain a competitive advantage by inhibiting the growth of neighbouring microorganisms, thus reducing competition for sparse resources (Cornforth & Foster, 2013). As microorganisms produce antibiotics, they have also evolved various defence mechanisms against them and against the toxic chemicals encoded/expressed by their competitors (Allen et al., 2010) in an endless ‘arms race’ (Baran et al., 2023). In nature, the balance between antibiotic production and their resistance is indeed locked into an equilibrium that prevents the wide dissemination of a particularly potent antibiotic. Likewise, it limits the proliferation of highly resistant strains within a population that would lead to the dysbiosis of microbial communities and loss of ecosystem functionality.

The most studied and known mechanisms that confer resistance to the lethal effects of antibiotics are those encoded by antimicrobial resistant genes (ARGs) (Alcock et al., 2019). These genetic elements provide the instructions for the synthesis of proteins or other molecules that counteract or neutralize the action of antibiotics as they mediate the export, inactivation of, or protection from antimicrobial compounds (Blair et al., 2015). Major categories of ARGs include those encoding for antibiotic efflux pumps, enzymes capable of degrading or modifying the antibiotics, molecules altering or protecting the antibiotic target site and capable of decreasing cell permeability to the antibiotic (Wilson et al., 2020). ARGs can be naturally present in bacterial populations or emerge through mutations in existing genes and can be efficiently transferred between cells via horizontal gene transfer (HGT) or increase in gene copy number clonally when encoded by plasmid (Allen et al., 2010). The presence of the same ARGs in different microorganisms within the same population also acts synergistically to reduce the antibiotic load below the minimum concentration needed to inhibit cellular growth, de‐activating its lethal effect through collective resistance (Vega & Gore, 2014). Theoretical studies show that the effectiveness of this strategy depends on the population death rate and speed of antibiotic removal through cellular binding or enzymatic degradation (Geyrhofer et al., 2023). Antibiotic efflux, by contrast, protects the individual cell by exporting antibiotic compounds back into the environment without altering the antibiotic itself, rendering neighbouring cells more susceptible to the compound. However, evidence suggests that ARGs may have had roles in cell signal trafficking or were selected for metabolic purposes, as in the case of efflux pumps that have roles in detoxification and act as ‘shields’ against harmful compounds, not solely antibiotics (Allen et al., 2010). Besides their versatility, ARGs can be highly mobilized throughout microbial populations via transformation, transduction and conjugation, greatly enhancing their dissemination (Zheng et al., 2023). A recent global analysis of topsoil communities showed a widespread prevalence of ARGs worldwide, with efflux pumps being the most common class (Delgado‐Baquerizo et al., 2022). This prevalence may be attributed to their rapid spread through the environment via aerosols, even in clouds, water runoff from agriculture and plastic waste. In addition to the widespread prevalence of ARGs, the presence of persister cells further exacerbates the challenge of combating antibiotic resistance. Indeed, persister cells, that is a subpopulation of dormant or slow‐growing bacterial cells that exhibit heightened tolerance to antibiotics, serve as reservoirs of resistance within microbial populations (Kussell et al., 2005). This dormancy allows them to survive antibiotic exposure and potentially contribute to the dissemination of antibiotic resistance genes in the environment.

WHAT ARE THE CONSEQUENCES OF ANTIBIOTIC MISUSE, OVERUSE AND RESISTANCE CO‐SELECTION?

While we anticipate encountering resistance against many naturally produced antibiotics, we should not see evidence of resistance to synthetic antibiotics in field surveys. However, this is not the case; the presence of the latest has often been detected in the environment (soil, water, etc.), suggesting that these compounds, and the resistance thereof, had expanded beyond clinical (or other) settings (Naidoo et al., 2020).

The release of antibiotics into natural ecosystems has introduced an additional ‘selective force’ that contributes to the pervasive problem of antibiotic resistance through the process of natural selection. When exposed to antibiotics, bacteria with (pre‐existing) resistance mechanisms survive and proliferate. This survival advantage, coupled with the ability of bacteria to share genetic material horizontally, facilitates the rapid spread of ARGs within and between bacterial species. Persistent low‐level exposure to antibiotic residues in the environment and resistance reservoirs in diverse settings sustain the presence and out‐of‐control spread of ARGs. These processes and conditions give birth to multidrug‐resistant (MDR) bacteria, colloquially referred to as ‘superbugs’, that evade many of our last‐line antibiotics and cause an estimated million deaths annually (de Kraker et al., 2016). Alexander Fleming anticipated this unfortunate scenario in his Nobel lecture when he stated, ‘…there is the danger that the ignorant man may easily underdose himself and by exposing his microorganisms to non‐lethal quantities of the drug make them resistant’.

The contemporary status of antibiotic resistance in clinical settings likely eclipses Fleming's worst concerns about drug‐resistant microorganisms. Today, we face the issue of the so‐called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) (De Oliveira et al., 2020), which are a collection of MDR bacteria that contribute most to community‐acquired infections of humans in hospitals. Notably, pathogenic bacteria, such as the aforementioned methicillin‐resistant S. aureus, pose a significant public health threat as part of the so‐called ‘hidden pandemic’ (Rezasoltani et al., 2020).

A current hypothesis is that antibiotic‐resistant bacteria not only evade death from antibiotic exposure but also access the cellular material left behind by susceptible cells that have perished. In the case of naturally competent bacteria, the ability to access extracellular DNA via natural transformation can be further stimulated by sublethal concentrations of individual stressors (e.g. pharmaceutical compounds including non‐antibiotics, by‐products of the chemical disinfection process and sunlight) (Augsburger et al., 2019; Mantilla‐Calderon et al., 2019; Wang et al., 2020). Many studies have reported increased natural transformation, with frequencies ranging from 1.2 to 4 times higher than control samples where the stressor is absent. The stimulation in natural transformation is due to changes in both translocation and integration steps. First, specific stressors can increase the translocation rates of extracellular DNA through the cell wall membrane either by upregulating the genes related to natural competence or by increasing the cell wall permeability (Augsburger et al., 2019; Wang et al., 2020). In other instances, specific stressors also increase the integration rates of the foreign DNA into the bacterium host's chromosome. In Acinetobacter baylyi ADP1, this is done through upregulation of the RecA recombination, which is triggered when the bacterium is actively repairing the damage induced by the presence of stressors (Augsburger et al., 2019). However, in the presence of multiple stressors, this stimulation in natural transformation frequencies does not always follow the geometric addition of responses associated with each stressor. Instead, the interactive outcome of stimulation of natural transformation frequencies can be either synergistic, neutral or antagonistic (Al‐Gashgari et al., 2023). This makes it difficult to predict when antibiotic‐resistant bacteria can access the extracellular material and how often such HGT events would occur. Hence, acting on the precautionary principle would be needed to alleviate such concerns. One example of such action is to determine the environmental influx of resistance genes that are present in the environment and to limit, therefore, the abundance of these genes that are available for HGT, for example, by binding them to soil clays and/or degrading these genes to such that they are no longer functional. Co‐selection of antibiotic resistance with other stressors further exacerbates these issues. Specifically, ARGs are commonly encoded on plasmids or other mobile genetic elements along with other useful genes (e.g. heavy metals detoxification), making the positive selection for these traits a new driver of ARGs' spread (Wang et al., 2021).

While accurately measuring the magnitude of the environmental influx of ARGs, known as resistome, poses challenges, efforts to quantify and compile have led to the establishment of ‘resistome surveillance’ (Alcock et al., 2019). Currently, extensive research on resistome is focused on soil (Delgado‐Baquerizo et al., 2022; Naidoo et al., 2023; Van Goethem et al., 2018), but further scientific investigation is warranted in other susceptible habitats and niches. These baseline assessments would provide insight into the contemporary status of microbial resistance to naturally occurring antibiotics within a specific niche. Deviations from these native ARG profiles would indicate exposure to new antibiotics, both from environmental microorganisms and synthetic sources like anthropogenic contamination. Monitoring this ‘dysbiotic state’ offers valuable insights for the search and discovery of new antibiotics.

WHERE (CAN) WE FIND NOVEL ANTIBIOTICS?

The dire need to uncover novel antibiotic chemistries is well‐known and stems primarily from a lack of funding by governmental agencies compared to other branches of medical research (Miethke et al., 2021), and from bacterial isolate screenings that typically identify the same classes of antibiotics repeatedly, that is to say that bacterial cultivation surveys continue to re‐encounter the same spectrum of fast‐growing isolates initially identified as candidates for antibiotic chemistries. Streptomyces species, for example, are some of the most commonly found bacteria in soil surveys (Miethke et al., 2021), and primary producers of the antibiotics we use to combat infection, including compounds like streptomycin and thiopeptide produced by edaphic Streptomyces species (Choksket et al., 2023).

To meet the ever‐increasing demand for novel antimicrobials, it is sensible to explore microbial niches in which competition between populations is highest. For instance, soil – from which most known antibiotic‐producing bacteria come – is one of the most complex environments on Earth. Due to the high heterogeneity in terms of chemical composition and nutrient content, as well as variations in pore size, water availability, anoxic conditions and influences from plants, among many other examples, soil harbours staggeringly different microbial consortia. Soil microbial communities vary from the micrometre scale, that is individual sand grains, to being driven by climatic regimes and pH across continental scales (Ladau & Eloe‐Fadrosh, 2019). The high level of microorganisms (biomass) and microbial lineages that can stably occupy soil niches intuitively means that competition should be equally high in the fight for survival. It is expected that the native soil microbiota comprising environmental bacteria (among other organisms such as archaea, viruses and fungi) are not under strong global selection for antibiotic resistance caused by the release of and exposure to antibiotics. Instead, long‐standing interactions between competing microorganisms should govern ARG prevalence in environmental soils, and we opine that this prevalence should be heightened in microbial hotspots, which are niches with high biomass and activity. For instance, the high cell abundance and limited resources, such as nutrients and space, of microbial hotspots drive intense competition among microorganisms (Bauer et al., 2018), here defined as ‘microbial oases of interactions’, continuously feeding the evolution of antibiotic production as a survival strategy (Svet et al., 2023). Edaphic examples of these hotspots are, among others, the rhizosphere (Figure 1) and biological soil crusts (BSCs). Moreover, expanding beyond terrestrial ecosystems, we find microbial hot spots in marine environments, such as the cases of marine snow (i.e. organic materials, such as dead or decaying marine organisms, faecal matter, tiny algae and other small particles that fall from the upper layers of the ocean to its depths), mangrove sediments and coral reefs. These microbial hotspots are particularly enriched in microbial cells when developed in extreme environments, such as harsh terrestrial ecosystems (deserts and drylands) and oligotrophic waters (Red Sea and brine pools). For example, the plant rhizosphere – the soil region directly influenced by plant roots – contains 3–4 orders of magnitude higher population density than surrounding bulk soils (Lv et al., 2023), which is exacerbated in deserts where nutrients (notably soil C, N and P) are limited (Marasco et al., 2022). While the rhizosphere microbiome is generally studied as a functionality and ecosystem service delivery hotbed, this microbial hotspot concomitantly hosts heightened intense competition between colocalized microorganisms for nutrients and space (Marasco et al., 2022). Likewise, in BSCs, cyanobacteria, heterotrophic bacteria, fungi and viruses share their immediate microniches, competing for nutrients and space (Van Goethem et al., 2019). It is important to note that novel environmental compartments emerging in the Anthropocene, such as the ‘plastisphere’, can also be considered microbial hotspots where microorganisms are enriched and form biofilms (Amaral‐Zettler et al., 2020). This new niche has proliferated extensively worldwide in recent decades as pervasive plastic pollution becomes a critical environmental concern (see other topics within this special issue). It forms a myriad of microniches (i.e. microplastics) dispersed throughout terrestrial and marine ecosystems, serving as reservoirs and refuges for ARGs and potential pathogens (Zadjelovic et al., 2023; Zhu et al., 2022). Moreover, the extended residence time in the environment and high microbial load can promote HGT among cells, accelerating the spill‐over and global spread of ARGs. Additionally, antibiotics themselves can act as selective niches for ARGs: for instance, a novel strain of Pseudomonas was isolated from a vial of the antibiotic hygromycin B, subsequently named P. hygromyciniae (Turner et al., 2023). This encounter underscores the resilience of microorganisms, as they continue to colonize even the most extreme niches in the relentless struggle for survival.

FIGURE 1.

FIGURE 1

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Comparison between a well‐known ‘microbial hotspot’ in the plant rhizosphere and bulk soil. These microbial microhabitats differ dramatically in their microbial load and access to nutrients. The rhizosphere (left part) features a dense community of interconnected microorganisms on soil particles (brown circles) vying for nutrients in the form of photosynthate (green shapes). We are of the opinion that the higher concentration of microorganisms at the root interface leads to higher levels of competition in the form of antibiotic production (red shapes). By contrast, the microbial biomass and interconnectedness of individuals in bulk soils (right part) are much less, leading to less emphasis on antibiotic production. The zoomed‐in view of a single sand grain shows differences in bacterial biomass (grey shapes), nutrients and antibiotics between a sand grain of rhizosphere (left side) and bulk soil (right side).

HOW CAN WE IMPROVE NOVEL ANTIBIOTIC DISCOVERY?

Despite significant advances in characterizing microbial communities and their constituents, a large proportion remains unexplored/overlooked. The microorganisms comprising microbial hotspots could yield/synthesize novel antibiotic compounds with different chemical structures or even undescribed mechanisms of action. This diversity is invaluable for overcoming antibiotic resistance mechanisms developed against existing antibiotics. For instance, according to cultivation efforts and molecular DNA‐based surveys, deserts are often numerically dominated by members of the Actinobacteriota. Certain genera within the Actinomycetes, and most notably species within the Streptomyces genus, are endowed with secondary metabolic capabilities, including antibiotic production (Watve et al., 2001). Streptomyces coelicolor is the model microorganism for secondary metabolism, including antibiotic production, and is a soil‐dwelling microorganism with a large genome comprising numerous biosynthetic gene clusters (BGCs) (Bentley et al., 2002). Shotgun metagenomics and whole‐genome sequencing are effective approaches for uncovering the genetic potential of microbial communities. Since these techniques continue to advance rapidly – as in the case of long‐read sequencer technologies developed by Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio), they facilitate the analysis of untapped genetic diversity (Alcock et al., 2019). At the same time, due to the continuous improvement of tools for novel chemistry discovery coupled with advancements in the application of artificial intelligence (AI) and machine learning algorithms to scientific endeavours, we now have greater chances than ever of unearthing the ‘hidden diversity of natural products’, including novel antibiotics (Mullowney et al., 2023). This synergistic approach not only expedites the screening process but also enhances our ability to predict the functional properties of potential antibiotics, accelerating the translation of metagenome‐derived insights into tangible solutions for combating emerging microbial threats. Yet, since it does not require the cultivability of microorganisms, it can be applied to the massive metagenome datasets already available online (Pavlopoulos et al., 2023), including those from the advocated ‘microbial oases of interaction’.

In addition to the discovery of novel molecules, the application of AI and machine learning facilitates biological activity prediction and drug design for molecular targets of interest (Mullowney et al., 2023). One example is the narrow‐spectrum antibiotic abaucin recently discovered using machine learning by screening chemical space for novel chemotypes against the MDR Acinetobacter baumannii (Liu et al., 2023). Similarly, machine learning has been applied to develop de‐novo antimicrobial peptides (AMPs) with broad‐spectrum antibiotic activity against MDR bacteria (Pandi et al., 2023). Metabolic modelling has also proven to be useful for identifying new antibiotic drug targets (Gwynne et al., 2023), as the possibility to identify microbe‐derived metabolites and relative producers without a priori knowledge recently implemented by the microbeMASST, a taxonomically informed mass spectrometry search tool (Zuffa et al., 2024).

In the realm of antibiotic discovery, the integration of metagenome data, advanced modelling techniques and AI holds immense promise for identifying novel antimicrobial molecules and pathways: it will be indeed critical to counter the discovery void of novel antibiotic classes over recent decades (at least since the 1980s).

ARE PHAGE THERAPIES AN ALTERNATIVE TO THE SHORTAGE OF ANTIBIOTICS?

Phage therapies could offer a viable alternative to the use of antibiotics in the treatment of bacterial infections. Historically, we have relied on a single class of medicines, that is antibiotics, that have direct actions on the bacteria. Phages, also called bacteriophages, are viruses that infect bacteria and hijack their cellular machinery to produce yet more phages. The association between phages and their corresponding host is usually intimate because bacterial species have specific viral predators (i.e. narrow phage specificity). This feature allows for targeted phage therapy, a centuries‐old technique determined exclusively by the infectious agent and generally prevents off‐target bacteria from being killed. This is unlike many antibiotics that have broad‐spectrum efficacies and hence kill both the pathogen (if susceptible) and other susceptible bacteria during treatment (altering the microbiome). Thus, phage therapies are particularly well suited for tackling MDR bacterial pathogens that are immune to antibiotics and, in future, could serve as a last‐line treatment in the event of complete antibiotic failure. An example of the use of phage against an MDR bacterial pathogen was demonstrated by Al‐Jassim and colleagues (Al‐Jassim et al., 2018) in which a pathogenic strain of Escherichia coli that is resistant to carbapenem (Mantilla‐Calderon et al., 2016) was demonstrated to become more sensitive towards sunlight in the presence of bacteriophages and hence die off much faster than in the absence of bacteriophages. The mechanism behind this observation was associated with the downregulation of cell wall functions, as well as functions related to scavenging and detoxifying reactive oxygen species and DNA repair (Al‐Jassim et al., 2018). The promise of phage therapy as a resurgent clinical technology is based on the fact that the phage cocktail can be tailored or personalized to the exact infectious bacterium based on broad screenings. In the future, we may become more targeted in our medicinal approaches, and rather than prescribing a broad‐spectrum antibiotic, we instead use medicines with a lower potential for the selection of resistance.

Soils are among the largest viral reservoirs on Earth. Soil viromes are currently receiving more attention than ever owing to an increased awareness of viral contributions to global biogeochemical cycling and the knowledge that phage therapies have high efficacy in containing antibiotic‐resistant bacteria through pathogen inactivation. This is important as antimicrobial agents spread to environmental soils. Bacteriophage therapy has been proposed to be used beyond the clinical settings (Fathima & Archer, 2021) to inactivate pathogens in the soil environment and has been used to counter invasive bacteria in the plant rhizosphere of agriculturally relevant crops (Ye et al., 2019). Direct polyvalent phage (phages capable of infecting more than one genus or species) application to contaminated soils reduced the levels of pathogenic E. coli and P. aeruginosa in lettuce crops and caused a dissipation of ARGs such as tetR and ampC. While the use of polyvalent phages may raise concerns of unintentional ecosystem impact, their application to the soil maintained the diversity and stability of the endemic soil bacterial community.

CONCLUSIONS

The release of antibiotics into the environment enhanced the selective pressure for the development of antibiotic resistance in naturally occurring bacteria. Resistant bacteria can survive and proliferate in the ecosystem, creating reservoirs of antibiotic resistance genes that can be transferred to other bacteria, including pathogens, contributing to the spread of antibiotic resistance and compromising the effectiveness of antibiotics in treating infections. While addressing antibiotic abuse and misuse in the context of environmental impact, we can work towards minimizing the contribution of human activities to the global challenge of antibiotic resistance and safeguarding ecosystems and human health. Here, we identify new targets of investigation for counteracting infectious diseases and preventing ARG spreads. Efforts to restore or maintain a balance between antibiotic production and ARGs would involve multifaceted strategies: (i) Search for novel antibiotics from microbial oases of interactions: We propose that the study of microbial oases of interactions has the potential to address the discovery of novel potential antibiotics. (ii) Antibiotic Stewardship: Responsible use of antibiotics in healthcare settings is essential to slow down the development of resistance. Proper dosing, duration and targeted use can help preserve antibiotic efficacy. (iii) Antibiotic Alternatives: Research into alternative antimicrobial strategies, such as phage therapy, antimicrobial peptides and immune‐based therapies, can reduce the selective pressure on bacteria while providing effective treatments. (iv) Regulation and Monitoring: Regulatory measures can be implemented to control the use of antibiotics in agriculture, aquaculture and other industries. Monitoring antibiotic usage and resistance patterns is crucial to inform policy decisions.

AUTHOR CONTRIBUTIONS

Marc W. Van Goethem: Conceptualization (equal); writing – original draft (equal). Ramona Marasco: Conceptualization (equal); supervision (equal); writing – original draft (equal); writing – review and editing (equal). Pei‐Ying Hong: Writing – review and editing (equal). Daniele Daffonchio: Writing – review and editing (equal).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ACKNOWLEDGEMENTS

D.D. acknowledges the financial support of King Abdullah University of Science and Technology (KAUST) through its baseline research funds. D.D. and P‐Y.H. also acknowledge the KAUST WDRC CCF funding FCC.1/1971‐44‐01. M.W.V.G. thanks A.E. Visser for her support and editing of an earlier draft of this manuscript.

Van Goethem, M.W. , Marasco, R. , Hong, P.‐Y. & Daffonchio, D. (2024) The antibiotic crisis: On the search for novel antibiotics and resistance mechanisms. Microbial Biotechnology, 17, e14430. Available from: 10.1111/1751-7915.14430

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