A new antibiotic blocked the lipoprotein transport system of bacteria

American scientists have developed the antibiotic lolamycin, which is active against Gram-negative bacteria. In experiments, it was active against more than 130 multidrug-resistant isolates and demonstrated efficacy in mouse models of pneumonia and blood poisoning. As reported in Nature, the antibiotic targets the bacterial lipoprotein transport system and does not significantly affect the gut microbiome.

Disruption of the gut microbiome due to antibiotic treatment can lead to colonisation by opportunistic microorganisms - such as Clostridioides difficile, which causes pseudomembranous colitis. Because the vast majority of clinically approved antibiotics are designed to target Gram-positive microorganisms, these drugs are detrimental to intestinal commensals. Even short-term exposure to clindamycin leads to long-term changes in the gut microbiome, affecting taxonomic composition and inducing selection of resistance genes.

Meanwhile, the effect of antibiotics targeting Gram-negative bacteria on gut microbiome disruption remains unclear, as such compounds are extremely scarce. The discovery or creation of such compounds is considered a challenge, as most potential targets for antibiotics are at non-specific bacterial receptors. It is also hindered by the complex structure of cell membranes of Gram-negative bacteria. The Lol system, a five-component protein system located in the periplasm that is responsible for transporting lipoproteins between the inner and outer membranes of Gram-negative bacteria, is considered a potential cellular target for the development of pathogen-specific antibiotics with a narrow spectrum of action.

A team of scientists led by Paul Hergenrother (Paul Hergenrother) from the University of Illinois at Urbana-Champaign was searching for an inhibitor of the Lol-system, which has antibiotic activity against Gram-negative pathogens. Through a series of experiments, the scientists identified inhibitors for all five components of the Lol-system, but prioritised compounds that interacted with the LolCDE transporter. Whole-cell analyses conducted at AstraZeneca in 2015 identified pyridinpyrazoles and pyridinimidazoles as inhibitors of the LolCDE complex. Chemical modifications using amination led to the development of lolamycin, which exhibited minimal toxicity to mammalian cell lines and red blood cells.

Experiments with various multidrug-resistant clinical isolates of bacteria (e.g., Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) showed that lolamycin exhibited selective antibacterial activity against Gram-negative bacteria and had no effect on Gram-positive bacteria or on opportunistic Gram-negative commensal bacteria. In mouse models, lolamycin treatment did not induce any significant changes in the taxonomic composition of the intestinal microbiota during the three-day course of treatment or subsequent recovery. There was also no increased risk of secondary C. difficile infection in mice.

Also, mouse models showed that lolamycin treatment was effective in pneumonia and septicaemia. Mice were infected with colistin-resistant E. coli. Mice treated with lolamycin showed a twofold reduction in bacterial load, and 100 per cent of the mice with sepsis survived.

According to the scientists, pathogen-specific antibiotics such as lolamycin will be crucial to minimise collateral damage to the gut microbiome. However, preclinical and follow-up clinical trials are needed to convince doctors of the safety and efficacy of lolamycin in humans.