Antibiotics have greatly improved infectious disease treatment, but their overuse has led to a global antibiotic resistance crisis. They also negatively affect the gut microbiota, which plays a crucial role in human health. This can have detrimental consequences for the host, especially in infants, as it can compromise gut immunity. Researchers have now developed a novel antibiotic, lolamicin, which shows significant promise in combating drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis. Unlike conventional antibiotics, lolamicin effectively targets pathogenic bacteria while sparing beneficial microbes in the gut. This groundbreaking finding was published in the journal Nature.
Muñoz and colleagues highlighted the harmful effects of traditional antibiotics. While effective in fighting infections, these drugs also eliminate beneficial bacteria, causing a range of health problems. Muñoz emphasized the need for next-generation antibiotics that target pathogenic bacteria without harming beneficial ones.
Antibiotic-related disruptions to the gut microbiome have been linked to increased vulnerability to further infections and various health issues, including gastrointestinal, kidney, and liver problems. Most current antibiotics either target Gram-positive bacteria or are broad-spectrum, eliminating both Gram-positive and Gram-negative bacteria. Gram-negative infections are particularly challenging to treat due to their double-layered cell walls, which provide robust protection against many antibiotics.
Muñoz et al. explained that certain drugs available to combat Gram-negative infections also eliminate beneficial gram-negative bacteria. Colistin, for example, is one such antibiotic but is associated with severe side effects, including C. difficile-associated diarrhea and toxic effects on the liver and kidneys. Hence, colistin is typically reserved as a last-resort antibiotic.
To address these issues, the research team focused on a series of drugs developed by AstraZeneca that inhibit the Lol system, a lipoprotein-transport mechanism unique to Gram-negative bacteria. Although these drugs initially required laboratory intervention to undermine bacterial defenses, they showed potential in discriminating between pathogenic and beneficial Gram-negative bacteria. This led the researchers to further explore these inhibitors.
The researchers designed various structural variations of the Lol inhibitors and tested their efficacy against Gram-negative and Gram-positive bacteria in cell cultures. Among these compounds, lolamicin emerged as a standout candidate, as it selectively targeted gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, without affecting Gram-positive bacteria. At higher doses, lolamicin eliminated up to 90% of the multidrug-resistant Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae clinical isolates.
Lolamycin is a macrolide antibiotic that inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome. This binding blocks the translocation step in protein synthesis, preventing the ribosome from moving along the mRNA and adding new amino acids to the growing polypeptide chain. As a result, bacteria are unable to produce essential proteins needed for their growth and survival, leading to a bacteriostatic effect where bacterial growth and multiplication are halted, allowing the host’s immune system to eliminate the infection.
In mouse models, lolamicin demonstrated remarkable efficacy, rescuing 100% of mice with drug-resistant septicemia and 70% of those with pneumonia. Extensive studies on the gut microbiome revealed that lolamicin did not cause significant changes in microbial populations, unlike standard antibiotics such as amoxicillin and clindamycin, which caused dramatic shifts and reduced the abundance of beneficial microbial groups.
The researchers noted that the mouse microbiome serves as a good model for human infections due to the similarity between human and mouse gut microbiomes. Studies have shown that antibiotics causing gut dysbiosis in mice produce similar effects in humans. Despite these promising results, researchers caution that many more years of research are needed to further validate these findings.
References
- Muñoz KA, Ulrich RJ, Vasan AK, Sinclair M, Wen PC, Holmes JR, et al. A Gram-negative-selective antibiotic that spares the gut microbiome. Nature. 2024 May 29;1–8.
- Patangia DV, Anthony Ryan C, Dempsey E, Paul Ross R, Stanton C. Impact of antibiotics on the human microbiome and consequences for host health. Microbiologyopen. 2022 Jan 13;11(1):e1260.
- Multi-drug resistant infections