'Smart', microbiome-sparing antibacterial therapy with a focus on the novel Lolamicin: an overview

Abstract

Purpose

Antibiotic resistance (AR) is an escalating worldwide health emergency, requiring inventive strategies for antibiotic treatment. This review examines the tactics used in designing smart antibiotics, with a specific emphasis on the mechanism of action of lolamicin, a newly developed microbiome-sparing antibiotic.

Methods

We review the recent advances in smart antibiotic development, particularly those aiming to preserve the gut microbiome while effectively targeting pathogens. The study focuses on lolamicin’s selective targeting mechanism, its inhibition of the LolCDE complex in Gram-negative bacteria.

Results

Lolamicin works by blocking the LolCDE complex, which is crucial for transporting lipoproteins in Gramnegative bacteria. It offers a significant improvement compared to conventional antibiotics and other microbiomesparing options by safeguarding the microbiome and reducing the development of resistance. However, its limited range of effectiveness — namely against certain harmful bacteria such as Pseudomonas aeruginosa — and the possibility of bacteria becoming resistant to it, remain areas of concern.

Conclusion

Lolamicin presents a hopeful resolution by selectively attacking Gram-negative bacteria while leaving the beneficial gut flora unharmed. Further investigation and rigorous clinical testing are essential to fully harness its promise and confirm its long-term utility in combating antibiotic resistance.

Introduction

Antimicrobial resistance (AR) represents a critical global health challenge, significantly complicating the management of infectious diseases, even in economically developed nations. According to the World Health Organization's Global Antimicrobial Resistance and Use Surveillance System (GLASS), data from 76 countries indicate that 42% of Escherichia coli strains are resistant to third-generation cephalosporins, while 35% of Staphylococcus aureus strains demonstrate methicillin resistance. Furthermore, in 2020, 20% of E. coli isolates causing urinary tract infection (UTI) exhibited reduced susceptibility to standard antibiotics, thereby impeding effective treatment [1]. This alarming trend of resistance is driven by the rising number of patients, surgical operations, and the extensive use of antibiotics, which, although effective against pathogens, simultaneously disrupt the gut microbiota [2]. This disruption fosters dysbiosis and facilitates the horizontal transfer of antibiotic-resistant genes (ARGs) between pathogenic and commensal bacteria [3]. Dysbiosis not only compromises intestinal defenses and prolongs recovery but also increases vulnerability to secondary infections and chronic disease states [4].

The gut microbiota plays a pivotal role in human physiology, contributing to nutrient metabolism, immune system maturation, and protection against pathogenic invasion via colonization resistance [5]. Antibiotic-induced dysbiosis perturbs these functions, leading to a cascade of adverse effects, including increased susceptibility to conditions such as allergies, viral infections, and secondary infections like Clostridioides difficile. Broad-spectrum antibiotics exacerbate these disruptions, causing systemic complications affecting gastrointestinal (GI), renal, and hematologic health [6].

The rise in AR incidence underscores the need for novel antimicrobial strategies that spare the gut microbiota while targeting resistant pathogens [1, 7]. While antimicrobial stewardship programs and personalized antibiotic regimens using pharmacokinetic and pharmacodynamic considerations hold promise, their isolated effects on the mitigation of resistance are still inadequate [6].

Emerging approaches, such as microbiome-sparing antibiotics, present a paradigm shift in the antimicrobial therapy. These agents exploit unique bacterial features, such as cell wall components or enzymatic pathways specific to pathogenic strains, to achieve selective targeting [8]. Precision delivery systems, such as antibiotic-loaded nanoparticles, further enhance this selectivity by releasing drugs exclusively in the presence of pathogenic bacteria [9]. Additionally, quorum-sensing inhibitors disrupt bacterial communication mechanisms, thereby attenuating virulence without compromising the microbiota [10].

Lolamicin, a recently discovered compound in 2024, shows selective activity against Gram-negative bacteria, often associated with multidrug resistance. This review delves into the discovery of lolamicin, its mechanism of action, advantages over other generic antibiotics, potential applications, and limitations [11].

“Smart” antibiotics target pathogens while sparing commensal microbiome

“Smart” antibiotics are designed to kill pathogens while minimizing indirect damage to beneficial gut-microbiome [12]. In order to achieve this, it is required to target bacterial features essential to certain pathogens, but either absent or insufficient in commensal microbes. Some strategies include focusing on the structural attributes of certain bacteria, e.g. Gram-negative outer membrane components or enzymes with significant sequence divergence between pathogenic and benign strains. For instance, many Gram-negative targets like DNA or protein synthesis enzymes are also present in Gram-positive bacteria, thus making broad-spectrum effects likely [7, 11]. Druggable targets that meet these criteria include components of the Gram-negative cell envelope and certain metabolic enzymes. For example, enzymes involved in the biosynthesis of lipopolysaccharides or lipoproteins, unique to Gram-negative bacteria, have been actively investigated as potential targets. A notable example is LpxC, an essential enzyme in the lipid A synthesis. Inhibitors of LpxC have demonstrated selective bactericidal activity against Gram-negative pathogens and have shown efficacy in preclinical models [11].

The novel “smart” antibiotic lolamicin, which is the focus of this review, exerts its mechanism of action by targeting the LolCDE transporter complex. This complex is essential for the translocation of lipoproteins to the outer membrane in Gram-negative bacteria. In contrast, Gram-positive bacteria lack this transport system completely, as they possess only a single membrane. Therefore, an antibiotic that targets LolCDE would inherently exhibit selectivity against Gram-negative bacteria while sparing all Gram-positive species [11].

What makes the novel lolamicin unique is its selectively to target Gram-negative pathogens by inhibiting the LolCDE ATP-binding cassette transporter, required for lipoprotein trafficking and outer membrane biogenesis but absent in Gram-positive bacteria. This dual selectivity enables lolamicin to differentiate not only between Gram-negative and Gram-positive bacteria but also between pathogenic and commensal Gram-negative species, reducing the chances for microbiome disruption. Notably, in vivo studies support that lolamicin does not significantly alter gut microbial diversity and, unlike conventional broad-spectrum antibiotics, allows the intact microbiome to resist C. difficile colonization. Given the significant burden of C. difficile infections, this microbiome-sparing feature represents a substantial clinical advantage. The low sequence homology of LolCDE between pathogens and commensals suggests that this selectivity-based approach may be further leveraged to develop pathogen-specific antibiotics against P. aeruginosa and Acinetobacter baumannii, two critical multidrug-resistant pathogens. By preserving gut microbiota while effectively eradicating resistant Gram-negative infections, lolamicin represents a paradigm shift in antibiotic development, offering a highly targeted, resistance-conscious therapeutic strategy [11].

Other potential narrow-spectrum targets under investigation include FabI (enoyl-ACP reductase) variants in staphylococci, which are required for S. aureus fatty acid synthesis but are not utilized by most gut bacteria [13]; DNA polymerase IIIC in clostridia, an enzyme absent in many other bacteria; and specific aminoacyl-tRNA synthetases in certain anaerobes [14]. By targeting such pathogen-specific vulnerabilities, smart antibiotics can achieve potent pathogen eradication while avoiding collateral damage to the microbiome.

The role of gram-specific targeting in "smart" antibiotics

An important discussion is whether antibiotics targeting only Gram-negative or Gram-positive bacteria, sparing the other group, can be considered “smart” in preserving the microbiome. While sparing one broad category, namely either Gram-positive or Gram-negative may help, but it is insufficient for maintaining microbiome balance. Narrow-spectrum antibiotics, such as vancomycin, are Gram-specific but can still disrupt the microbiome. Vancomycin targets Gram-positive organisms and eliminates beneficial Firmicutes (e.g., Lactobacillus and Clostridium species), which may promote dysbiosis and opportunistic infections like C. difficile, despite leaving Gram-negative bacteria intact. Similarly, antibiotics targeting only Gram-negatives, like colistin, can disturb the microbiome by eradicating beneficial Gram-negative commensals such as Bacteroides and Proteobacteria, potentially leading to dysbiosis and opportunistic Gram-positive infections [15, 16].

Thus, to be truly "smart," an antibiotic must have more precise specificity and mechanism of action. Lolamicin may serve as an instructive example. While it is designed to target Gram-negative bacteria, its “smart design” ensures that it does not harm beneficial Gram-negative gut flora, preserving essential microbiome diversity. This is achieved through its selective action against Enterobacteriaceae pathogens via the LolCDE target, which is absent or divergent in most gut commensals. Ultimately, lolamicin represents an exemplary "smart" antibiotic because it minimizes disruption to the microbiome, focusing on pathogenic Gram-negatives while sparing beneficial species, in contrast to more generalized Gram-specific antibiotics. In essence, a smart antibiotic should ideally preserve both major groups of the microbiome, avoiding collateral damage across the entire healthy gut microbiome composition [11, 16].

The healthy gut microbiome composition

The human gut microbiome consists of hundreds of bacterial species that coexist in a healthy host. In the colon of an average adult, two bacterial phyla, Firmicutes and Bacteroidetes, dominate, accounting for approximately 90% of the gut microbiota [17].

Firmicutes include several genera, such as Lactobacillus, Clostridium (which encompasses many beneficial Clostridial species), Ruminococcus, and Faecalibacterium. Bacteroidetes (Gram-negative) are primarily represented by the genus Bacteroides (e.g., Bacteroides fragilis) and Prevotella [17].

Other bacterial phyla, including Actinobacteria (e.g., Bifidobacterium species), Proteobacteria (e.g., certain strains of Escherichia coli), Verrucomicrobia (e.g., Akkermansia muciniphila), and Fusobacteria, are present in smaller proportions but contribute immensely to the overall microbiome composition. This balanced microbial community plays a crucial role in various physiological processes, including digestion, the synthesis of vitamins and short-chain fatty acids, the modulation of the immune system, and the prevention of pathogen colonization through a phenomenon known as "colonization resistance" [17, 18].

A diverse microbiome, characterized by a wide variety of beneficial anaerobes such as Faecalibacterium prausnitzii (Firmicutes) and Bacteroides species, is typically regarded as a hallmark of a healthy gut ecosystem. It is essential to emphasize that the health of the microbiome is not determined by the Gram staining characteristics of its bacterial members. While Firmicutes are predominantly Gram-positive and Bacteroidetes and Proteobacteria are mostly Gram-negative, both Gram-positive and Gram-negative bacteria can play beneficial roles within the gut. For example, Bifidobacterium (Gram-positive Actinobacteria) and Akkermansia (Gram-negative Verrucomicrobia) are recognized as beneficial gut residents. Hence, a healthy microbiome is defined not by the Gram status of its components but by the functional diversity and synergistic interactions of microbial populations that collectively contribute to host health [17, 18].

Experimental approaches for categorizing “smart” antibiotics

In vitro evaluation of narrow-spectrum activity and microbial selectivity

To establish whether a candidate antibiotic exhibits "smart" antimicrobial properties, comprehensive in vitro assessments are conducted. A pivotal component of this evaluation is spectrum-of-activity profiling, wherein the minimum inhibitory concentration (MIC) is determined against: (i) the intended pathogenic targets, (ii) a representative panel of commensal gut bacteria (spanning Gram-positive and Gram-negative species), and (iii) potential off-target pathogens. A truly microbiome-sparing antibiotic should demonstrate potent activity against its designated pathogens while exhibiting minimal inhibitory effects on commensal microbiota at clinically relevant concentrations. For instance, the experimental antibiotic lolamicin displayed strong efficacy against E. coli and other Enterobacteriaceae but had negligible impact on commensal Bacteroides and Gram-positive anaerobes, underscoring its selective mechanism of action [11].

Further validation is achieved through biochemical and genomic analyses, which assess target-specific interactions. Comparative studies of binding affinity and inhibitory potency for the drug’s target across different bacterial species can elucidate selectivity. In the case of lolamicin, structural variations in the LolCDE transporter between pathogenic and commensal strains contributed to its preferential activity. Additionally, resistance induction studies—where pathogen-derived mutants are sequenced to identify target-associated mutations—can confirm mechanistic specificity. The absence of such mutations in commensals suggests a low propensity for collateral damage or resistance development in the gut microbiota. Together, these in vitro approaches (MIC profiling, binding assays, and resistance genetics) provide foundational evidence of an antibiotic’s precision before progressing to in vivo testing [11].

In vivo validation: the clostridioides difficile challenge model

The most compelling evidence for microbiome-sparing antibiotics emerges from in vivo models, where the complex interplay between host, microbiota, and pathogen can be fully assessed. Among these, the C. difficile infection (CDI) challenge model serves as a gold standard for evaluating microbiome preservation. This model capitalizes on the well-established phenomenon whereby antibiotic-induced dysbiosis predisposes hosts to C. difficile overgrowth and subsequent colitis [19].

In a typical experimental design, animals (mice or hamsters) are administered the test antibiotic, followed by exposure to C. difficile spores. Broad-spectrum antibiotics, such as clindamycin, rapidly deplete protective gut flora, rendering animals susceptible to fulminant CDI and mortality. In contrast, a microbiome-sparing antibiotic should maintain colonization resistance, allowing the host to clear the pathogen without disease. For example, lolamicin-treated mice resisted C. difficile infection as effectively as untreated controls, whereas animals receiving conventional broad-spectrum antibiotics succumbed to severe colitis. Similarly, fidaxomicin—a narrow-spectrum macrocyclic antibiotic—has demonstrated superior microbiome preservation compared to vancomycin in both preclinical and clinical settings, correlating with reduced CDI recurrence [19].

The C. difficile challenge model offers a functional readout of microbiome integrity, moving beyond taxonomic profiling to assess physiological resilience against pathogen invasion. Given its translational relevance, this model is frequently employed in early-stage development of selective antibiotics. Regulatory agencies also recognize its predictive value, as agents that mitigate C. difficile susceptibility may offer a clinically meaningful advantage in reducing antibiotic-associated complications [19].

Breakthroughs in smart antibiotic design

The period between the 1940s and 1960s marked the golden age of antibiotic discovery, during which numerous novel antibiotic classes were identified. However, since that time, no new antibiotic classes have been discovered. Despite the promise of antibiotics like penicillin, concerns about bacterial resistance emerged early on. In 1940, Abraham and Chain first demonstrated that a strain of E. coli could inactivate penicillin by producing penicillinase, an enzyme capable of degrading the drug [20].

Disruption of the gut's natural immunity, maintained by the gut microbiome, is closely linked to the development of antibiotic resistance and recurrent infections. The widespread use of antibiotics exacerbates this issue by altering the microbial composition and weakening the intestinal mucosal barrier, increasing susceptibility to infections and inflammation. Long-term antibiotic use reduces microbial diversity and contributes to dysbiosis, which has been associated with complex diseases such as inflammatory bowel disease (IBD) [21]. The concept of dysbiosis dates back to the pioneering work of Dutch scientist Antonie van Leeuwenhoek in the seventeenth century, who first observed microbial communities, laying the foundation for understanding how changes in the microbiota can influence health [22].

Several antimicrobial drugs, as well as innovative techniques have been implemented to target bacterial pathogens, with the potential to preserve the host’s gut microbiome and mitigate the emergence of antibiotic resistance:

• Lolamicin, reported in 2024, is a novel antibiotic that inhibits the LolCDE complex in Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae). Its microbiome-sparing properties and novel mechanism make it a promising candidate for future therapies [11].

• SMT-738 targets the LolC/E complex in Enterobacteriaceae, showing selective Gram-negative activity while preserving commensals, though clinical data remain limited [23].

• Afabicin, the most advanced FabI inhibitor, targets S. aureus while sparing microbiota, though its narrow spectrum limits applications [13].

• Debio 1453 inhibits fatty acid synthesis in Neisseria gonorrhoeae and Chlamydia trachomatis, offering microbiome preservation with oral/intramuscular formulations [24].

• FP-100 (hygromycin A) selectively targets Borrelia burgdorferi and periodontal pathogens without disrupting beneficial gut bacteria [25].

• FtsZ inhibitors (TXA707/TXA709) disrupt cell division in drug-resistant Gram-positive bacteria, showing synergy with β-lactams [26].

• Ribaxamase protects gut flora from IV β-lactams by degrading excess antibiotics in the GI tract, currently in Phase 1b/2a trials [27].

• Fidaxomicin, FDA-approved in 2020, selectively targets C. difficile RNA polymerase while preserving intestinal microbiota [28].

• Ibezapolstat shows 100% cure rates for CDI in trials while maintaining microbiome diversity, now in Phase 2b [29].

• Ridinilazole binds C. difficile DNA with precision, demonstrating superior microbiome preservation versus vancomycin [30].

Several microbiome-sparing agents and techniques demonstrate therapeutic potential. CRS3123, a small-molecule inhibitor of methionyl-tRNA synthetase, selectively disrupts C. difficile protein synthesis while sparing commensal species [31]. Bacteriophages are viruses that specifically infect and kill bacteria—eliminate target pathogens with minimal microbiome disruption, though strain-specific matching limits broad application [32]. Chimeric peptides, which combine antimicrobial domains with targeting sequences, selectively disrupt pathogen membranes and demonstrate particular efficacy against biofilms and drug-resistant strains [33]. Prodrugs (e.g., β-lactam-activated conjugates) exploit bacterial enzymes for localized activation, thereby minimizing off-target effects [34]. Antimicrobial nanoparticles (e.g., silver, TiO₂) induce bacterial death through membrane disruption or reactive oxygen species generation, though cytotoxicity concerns persist [9]. CRISPR-based systems utilize programmable nucleases to precisely edit bacterial genomes, disabling resistance genes while preserving commensal microbiota [35]. Quorum sensing inhibitors attenuate virulence by disrupting bacterial communication pathways rather than through bactericidal activity, thereby maintaining microbiome diversity [10]. Emerging approaches such as peptide nucleic acids (PNAs)—synthetic oligonucleotide analogs that inhibit essential gene expression—show promise but require further development to overcome delivery challenges and achieve clinical scalability. While these diverse strategies collectively address the critical need for microbiome preservation during antimicrobial therapy, most remain in preclinical or early clinical development, necessitating additional optimization for therapeutic implementation [36].

The overview of microbiome-sparing antibiotics and gut microbiome-sparing techniques to combat bacteria discussed in this review are presented in Table 1. It summarizes their mechanisms of action, targeted pathogens, advantages, and disadvantages. The comparison demonstrates the potential of these agents in addressing antibiotic resistance.

Table 1.

Examples of microbiome-sparing antimicrobial agents

Name	Mechanism of Action	Pathogens Targeted	Advantages	Disadvantages
Lolamicin	Inhibits LolCDE complex, essential for lipoprotein transport in Gram-negative bacteria	Gram-negative bacteria (E. coli, K. pneumoniae, E. cloacae)	Preserves microbiota, novel mechanism	Limited to Gram-negative pathogens, not effective against P. aeruginosa or A. baumannii
SMT-738	Targets LolC/E complex in Enterobacteriaceae	Gram-negative pathogens (Enterobacterales)	Microbiome-sparing, selective targeting	Early-stage development, limited clinical data; mainly selective for Enterobacterales
Afabicin	Inhibits FabI, an enzyme in fatty acid biosynthesis	S. aureus (Gram-positive bacteria)	Microbiome-sparing, targets Gram-positive pathogens	Narrow-spectrum, only effective against Gram-positive bacteria
Debio 1453	Inhibits FabI, disrupting fatty acid biosynthesis	N. gonorrhoeae	Microbiome-sparing, rapid bactericidal activity	Limited data, in development stage
FP-100 (Hygromycin A)	Inhibits ribosomes of spirochetes	B. burgdorferi, Treponema pallidum, Fusobacterium nucleatum	Selectively targets periodontal pathogens without disrupting beneficial bacteria (Streptococcus parasanguinis, Bifidobacterium longum)	Still under development, limited data
FtsZ Inhibitors (e.g. TXA707, TXA709)	Inhibit polymerization of the FtsZ protein, disrupting bacterial cell division	Drug-resistant Gram-positive bacteria (MRSA, VRSA, DNSSA)	Synergistic with β-lactams, microbiome-sparing	Limited to Gram-positive pathogens, limited data
Ribaxamase	β-lactamase that targets excess IV β-lactam antibiotics in the GI tract	Prevents damage from broad-spectrum antibiotics in gut flora	Reduces dysbiosis, prevents antibiotic resistance and C. difficile infection	Limited to co-administration with IV β-lactams, early trial phase
Fidaxomicin	Inhibits bacterial RNA polymerase, disrupting transcription	C. difficile	Targets C. difficile, microbiome-sparing	Narrow-spectrum, limited to C. difficile infections
Ibezapolstat	Targets DNA polymerase IIIC (Pol IIIC)	C. difficile	100% clinical cure rate in trials, microbiome-sparing	Early-stage trials, high cost
Ridinilazole	Binds to minor groove of DNA, inhibiting transcription	C. difficile	Targets C. difficile, microbiome-sparing	Limited to C. difficile infections, i.e. narrow-spectrum

Mechanism of Action of Lolamicin [11]

Lipoprotein Transport in Gram-negative Bacteria: In Gram-negative bacteria, lipoproteins are essential components transported to the outer membrane via the localization of the lipoproteins (Lol) system. The Lol system includes five proteins: LolA, LolB, and the LolCDE complex. The LolCDE, an ABC transporter, releases lipoproteins from the inner membrane and transfers them to LolA, a periplasmic chaperone. LolA then transfers the lipoproteins to LolB, which inserts them into the outer membrane.

Targeting the Lol System: Lolamicin disrupts the LolCDE complex, essential for lipoprotein transport in Gram-negative bacteria. By inhibiting LolCDE, lolamicin prevents lipoproteins' release and subsequent transport from the inner membrane to the outer membrane.

Action on LolCDE Complex: The compound's interference with the LolCDE complex hinders its ability to release outer-membrane-specific lipoproteins. This disruption in lipoprotein transport impairs the outer membrane integrity and functionality, leading to bacterial cell death.

Molecular Interactions, Binding Site and Mechanism: The target is the LolCDE complex, specifically binding within the lipoprotein transport pathway. Resistance mutations identified in LolC and LolE proteins confirm these as primary targets, with mutations leading to resistance by altering the binding site. Structural studies, including molecular modeling and cryo-electron microscopy, indicate that lolamicin binds to sites overlapping with the native substrate Lpp lipoprotein at its fatty acid chains. Key residues involved in binding include D264/I268/Y366 of LolE, with mutations at these sites impacting lolamicin binding and resistance. Lolamicin forms hydrophobic interactions with nonpolar or aromatic residues in the binding pocket, which is essential for its inhibitory action. Mutations that disrupt these hydrophobic interactions reduce lolamicin's efficacy. This binding blocks the lipoprotein's regular interaction with LolCDE, halting lipoprotein transport and leading to bacterial cell death. The mechanism of action of Lolamicin is described in Fig. 1.

Fig. 1.

Lolamicin exhibits selective activity against Gram-negative ESKAPE pathogens, including E. coli, K. pneumoniae, and E. cloacae, by targeting the LolCDE complex. It binds to major sites BS1 and BS2 (LolC/LolE, residues D264, I268, Y366), and transient sites TS1 and TS2, disrupting lipoprotein transport to the outer membrane. The killing mechanism hinges on the accumulation of lipoproteins which ultimately leads to cell death

Advantages of Lolamicin over other antibiotics and their alternatives

Lolamicin's broad yet specific targeting of Gram-negative pathogens sets it apart from other smart antibiotics, offering a more comprehensive application while maintaining microbiome integrity. Its unique properties offer several promising advantages over other antimicrobial treatments, including broad-spectrum antibiotics, plant-based substances, probiotics, and other microbiome-sparing antibiotics currently in development. For instance, it targets a slightly broader range of Gram-negative pathogens, including ESKAPE pathogens, compared to substances such as SMT-738, which focuses more narrowly on Enterobacterales [11, 23].

In the evolving landscape of antibiotic development, the focus has shifted toward creating treatments that target specific pathogens and spare the microbiome. This is critical in reducing side effects and combating antibiotic resistance. Lolamicin offers several advantages over other gut microbiome-sparing antibiotics currently in development. One key advantage of lolamicin is its selective targeting of pathogens. This selectivity arises from its specific inhibition of the LolCDE transport system, which exhibits significantly lower sequence homology in commensal Gram-negative bacteria compared to pathogenic strains, enabling precise antimicrobial action while preserving beneficial gut microbiota. For instance, ridinilazole, in Phase III trials, targets C. difficile but does not address infections caused by Gram-negative bacteria [30]. Similarly, afabicin, in Phase II development, targets FabI in S. aureus for treating skin infections but is limited to Gram-positive pathogens. AR-101 (mAb), targets P. aeruginosa for hospital-acquired pneumonia and ventilator-associated pneumonia, using a monoclonal antibody to target a specific serotype, thus sparing other bacteria but limiting its application [37]. In contrast, lolamicin targets a broader range of Gram-negative bacteria, including multidrug-resistant strains like E. coli, K. pneumoniae, and E. cloacae, making it versatile for treating various infections without disrupting the gut microbiome [11].

While ridinilazole and afabicin reduce resistance through specific mechanisms, they remain susceptible to resistance via genetic mutations [30]. Monoclonal antibodies like AR-101 face resistance from antigenic variation [37]. By targeting the LolCDE complex within the lipoprotein transport system, lolamicin may reduce cross-resistance with other antibiotic classes, unlike the aforementioned antimicrobial substances [11].

Lolamicin also excels in preserving the microbiome. Ridinilazole and afabicin were designed to spare the gut microbiome by targeting specific pathogens but are restricted to particular infections. AR-101 preserves the microbiota but is limited to P. aeruginosa. Lolamicin preserves beneficial gut microbiota while offering broad application across Gram-negative infections, maintaining gut health while effectively treating infections.

Comparing lolamicin with other alternatives further highlights its advantages. SMT-738, in preclinical development by Summit Therapeutics, targets the LolC/E complex in Enterobacteriaceae for bloodstream and complicated urinary tract infections (cUTI). Like lolamicin, SMT-738 aims to spare the microbiome but is still in the early stages of development. Debio 1453, also in preclinical stages by Debiopharm, targets FabI in N. gonorrhoeae for treating gonorrhea, preserving the microbiome but being pathogen-specific. Various antisense agents, such as peptide conjugate–peptide nucleic acids (by Techulon Inc.), target specific gene translation in MRSA, A. baumannii, and P. aeruginosa but are still far from clinical use [36]. EB004 (CRISPR phage) by Eligo Bioscience, also in preclinical stages, targets specific antibiotic resistance genes in Enterobacteriaceae, offering precise decolonization of antibiotic-resistant bacteria but facing challenges in clinical application [11].

When comparing lolamicin with other smart antibiotics that preserve the microbiome, it can be deduced that lolamicin combines broad-spectrum efficacy with microbiome preservation. These attributes make it a significant advancement in antibiotic therapy. However, further clinical validation is essential to establish its safety and effectiveness across diverse patient populations and infection types.

Limitations of Lolamicin

The rate at which bacteria become resistant to a particular antibiotic is referred to as "frequency of resistance" (FoR) [38]. A high FoR suggests that germs can quickly develop defenses against the medication, which eventually reduces its effectiveness as resistant strains multiply. On the other hand, a low FoR indicates that bacteria have a lower propensity to become resistant, extending the antibiotic's utility. In the case of lolamicin, while laboratory studies indicate a low FoR, suggesting a promising profile in this regard, it is essential to note that no antibiotic is entirely immune to resistance [39]. This means that lolamicin, like other antibiotics, may also be associated with some level of antibiotic resistance, namely with point mutations. Thus, to further increase the drug's resilience against the emergence of bacterial resistance, researchers are working to improve the FoR through "chemical synthesis and lead optimization" [11].

The fact that lolamicin is highly specific for certain pathogens, particularly Enterobacteriaceae, might also be considered a potential downside. While narrow-spectrum antibiotics can be beneficial in decreasing the risk of secondary infection due to microbiome disruption (kills beneficial bacteria → opportunistic pathogens proliferate and cause disease) [8] and the potential for widespread resistance development [40], their limited range prevents it from being used against a greater variety of illnesses. Neither non-pathogenic Gram-negative commensal bacteria nor Gram-positive bacteria are targeted by lolamicin. Thus, less versatility might limit its use in various clinical settings. For example, it may not be suitable for treating complex infections involving multiple bacterial species [11].

Another factor that one might take into consideration when it comes to the limitations of lolamicin is its lack of efficacy against wild-type or efflux-deficient strains of P. aeruginosa and A. baumannii, which further limits its clinical utility [11]. These two pathogens are notorious for their multidrug resistance and are responsible for severe infections, particularly in hospitals [41].

It is worth mentioning that even lolamicin may also be associated with some antibiotic resistance, i.e. point mutations at residues lining BS1 and BS2, as observed in the resistance mutation studies. Therefore, there needs to be intelligent and regulated antibiotic use, because even antibiotics with much less potential to cause resistance may become a problem. Potential side effects, toxicity, interactions, and contraindications of lolamicin are currently unknown, but essential considerations for any new antibiotic and thus require further investigation [11].

Conclusion

The increasing danger posed by antibiotic resistance necessitates the development of novel antimicrobial tactics that specifically focus on combating resistant organisms while minimizing harm to the microbiome. This highlights the immediate need for innovative approaches that possess unique mechanisms of action during this age of resistance. However, the “smart” antibiotics provide some potential lead compounds against bacterial resistance. Despite the existing knowledge, we maintain the belief that the advancement in innovation and technology will one day overcome the problem of antimicrobial resistance.

Lolamicin is a very promising development in this area, since it specifically targets Gram-negative bacteria by inhibiting the LolCDE complex responsible for transporting lipoproteins. Lolamicin's unique specificity enables it to effectively target and eliminate strains of bacteria such as E. coli and K. pneumoniae, while also protecting the gut microbiome. This characteristic gives it a notable advantage over conventional broad-spectrum antibiotics.

Subsequent investigations should prioritize gaining a deeper understanding of the pharmacodynamics and pharmacokinetics of lolamicin, as well as exploring its possible adverse effects, toxicity, and interactions with other medications. The advancement is significant, but it is essential to continue innovating and conducting rigorous clinical trials to fully exploit its potential and maintain its effectiveness in the ongoing fight against resistant microorganisms.

Author contributions

All authors contributed equally to the conception, drafting, and revision of this manuscript. Each author has read and approved the final manuscript for submission.

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The authors declare that no funds, grants, or other financial support were received during the preparation of this manuscript.

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