New antibiotic to combat growing threat of drug resistance
Key Takeaways
Antibiotic resistance is a growing challenge, especially with gram-negative bacteria that cause many hospital-acquired infections.
Traditional broad-spectrum antibiotics often disrupt the gut microbiome, leading to complications like secondary Clostridioides difficile infections.
Lolamicin is a new gut-friendly antibiotic that targets the lipoprotein transport system in gram-negative bacteria; it fights over 130 multidrug-resistant strains, protects the gut microbiome, and has shown effectiveness in mouse models of pneumonia and septicemia.
Current antibiotics often lack specificity, affecting both harmful and beneficial bacteria in the gut, which increases the risk of secondary infections and contributes to the development of antibiotic resistance. This non-selective disruption has also been linked to longer-term health issues, including colon cancer and irritable bowel syndrome.[][][]
At the same time, the indiscriminate use of antibiotics has also given rise to life-threatening multidrug-resistant gram-negative bacteria—it has been estimated that by the year 2050, there will be over 10 million annual fatalities due to antimicrobial resistance (AMR).[] Antibiotic resistance poses a significant threat to global health, particularly with the rising prevalence of multidrug-resistant (MDR) gram-negative bacteria.
Given these challenges, developing selective antibiotics that spare the gut microbiota has become a critical focus in the fight against antibiotic resistance. But lolamicin, a new and novel antibiotic, presents a promising solution to this growing threat.[]
Challenges with traditional antibiotics
Antibiotic-associated diarrhea (AAD) remains a prevalent issue stemming from antibiotic use, with disruptions to gut microbiota leading to overgrowth of pathogens like Clostridioides difficile, Klebsiella, Staphylococcus, and Candida.[]
Notably, C. difficile is implicated in 15%–25% of AAD cases, which can escalate to severe complications such as toxic megacolon and intestinal perforation. The CDC has flagged C. difficile as an urgent antibiotic-resistant threat due to its severity and the increasing prevalence linked to indiscriminate antibiotic use.
AMR is a growing threat to global health, as is the rising prevalence of MDR—the latter being a major cause of nosocomial infections.
The CDC has identified several high-risk AMR pathogens, including MDR Pseudomonas aeruginosa, Carbapenem-resistant Enterobacterales (CRE) and Acinetobacter, methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus (VRE), extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, and emerging drug-resistant fungal infection Candida auris (C. auris).[] Four out of these seven infections are gram-negative, requiring heavy antibiotics with the potential to disrupt the normal flora of the gastrointestinal tract.
Lolamicin: A novel, selective antibiotic
A recent study published in Nature introduces lolamicin, a novel antibiotic specifically targeting gram-negative bacteria without disrupting beneficial gut flora, which is a welcome option given the current limitations of antibiotic therapies.[]
Mechanism of action and selectivity
Lolamicin uniquely targets the lipoprotein transport system (Lol pathway), essential for the survival of gram-negative bacteria, as it facilitates the movement of lipoproteins between their inner and outer membranes.
This pathway is absent in gram-positive bacteria, which lack the dual-membrane structure and only possess a single cellular membrane. As a result, lolamicin offers double selectivity—attacking pathogenic gram-negative bacteria while preserving gut commensals, thus minimizing collateral damage—overcoming a key limitation of traditional antibiotics.[][]
Preclinical efficacy and safety
Lolamicin has demonstrated robust efficacy in preclinical trials, including multiple mouse models of acute pneumonia and septicemia. It selectively targeted multidrug-resistant strains of E. coli, Klebsiella pneumoniae, and Enterobacter cloacae, achieving up to 90% bactericidal activity in cell cultures. In vivo, orally administered lolamicin improved survival rates in septicemia models, with a 70% survival rate among treated mice. Notably, lolamicin-treated mice exhibited significantly lower C. difficile colonization than those receiving broad-spectrum antibiotics like amoxicillin or clindamycin.[]
While these preclinical findings are promising, lolamicin is still in early-stage development. Human clinical trials are necessary to confirm its efficacy and safety profile, as well as to evaluate the potential for resistance development against this novel mechanism.
Interim strategies for gut health during antibiotic use
While waiting for microbiome-sparing antibiotics like lolamicin to reach clinical use, there are immediate steps that can be taken to mitigate the impact of conventional antibiotics on gut health. Consider the following:
Antimicrobial stewardship (AMS)
Stewardship entails using the right antibiotic at the right dose, drug route, and duration, and de-escalating therapy promptly when appropriate. According to a review from Cureus, this approach both preserves antibiotic efficacy and minimizes gut microbiota disruption.[]
Dietary interventions
High-fiber diets support the rapid recovery of healthy gut flora post-antibiotic treatment. In fact, as noted in a 2022 study on American adults, consuming a high-fiber diet was associated with a lower risk of AMR and a lower abundance of Clostridium overgrowth.[]
Probiotics and fermented foods
The role of probiotics during antibiotic use shows mixed results:
A 2024 trial found that probiotics containing Lactobacillus, Bifidobacterium, and Saccharomyces strains helped maintain gut microbiome diversity, increased Bacteroides, reduced enterobacteria, and decreased AMR genes in adult patients on antibiotics.[]
Similar outcomes were observed in a 2024 study published in JAMA Network Open, involving pediatric patients on antibiotic therapy who were given a multispecies probiotic with eight bacterial strains; compared with controls, the probiotic temporarily boosted microbial diversity—but the improvement was minor and results short-lived.[]
However, consuming probiotics from natural sources like yogurt, kefir, and sauerkraut is a practical and beneficial way to support gut balance during and after antibiotic treatment.
What this means for you
Preserving gut microbiota integrity helps preserve gastrointestinal functions and prevents antibiotic-associated diarrhea and other gastric dysfunctions. Lolamicin or related compounds targeting the Lol system could offer a promising way to treat gram-negative infections without disrupting the gut microbiome. But until these new antibiotics are readily available, the focus should be on using antibiotics smartly—the right choice, the right dose, and for the right amount of time—to fight resistance and protect your patients' gut health.