New antibiotic targets only gram-negative bacteria, sparing the gut

A team led by Paul Hergenrother at the University of Illinois Urbana-Champaign has discovered a new antibiotic that exclusively targets gram-negative bacteria and avoids wiping out the ecosystem of other microbes that flourishes in the gut.

Lolamicin, as the group has named the compound, targets part of the localization of lipoprotein (Lol) pathway, a protein system that’s responsible for the transport of lipoproteins to the outer membrane in gram-negative bacteria. Specifically, the molecule interferes with the LolCDE complex, disrupting its ability to release outer-membrane-specific lipoproteins from the inner membrane (Nature 2024, DOI: 10.1038/s41586-024-07502-0).

Lolamicin was especially effective against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae in mice. Importantly, the antibiotic also appeared to leave commensal bacteria alone, since many are gram-positive bacteria that don’t have the Lol complex that lolamicin exploits. That spared the mice from gut dysbiosis—a common side effect of broad-spectrum antibiotics—and prevented colonization by Clostridioides difficile, opportunistic pathogens that can take over the intestinal tract when antibiotics wipe out their natural competitors.

“I think there’s an enhanced appreciation now of what antibiotics are doing for all of us. Beyond curing us from infection, there’s a whole host of deleterious effects,” Hergenrother says. “Basically every [US Food and Drug Administration]-approved antibiotic out there is causing gut dysbiosis. It’s killing commensal bacteria, the good bacteria, as it kills the pathogen.”

Hergenrother’s lab began the work that led to lolamicin’s discovery around 2019. The researchers started with two types of compounds—pyridine pyrazoles and pyridine imidazoles—that scientists at AstraZeneca had identified as potential drugs for gram-negative Escherichia coli back in 2015 but chose not to advance. Those compounds lacked solubility, weren’t as effective inside the body as in in-vitro models, and had a high rate of resistance. The Hergenrother team—in particular Kristen A. Muñoz, then a graduate student and lead author on the Nature paper—modified the compounds identified by the AstraZeneca group by changing their scaffolds through an iterative approach, ultimately arriving at lolamicin.

Gram-negative bacteria are notoriously difficult to drug because of their tough outer membranes. Existing antibiotics have a hard time getting through, and many of those that do are tossed right back out by efflux pumps or blocked by bacterial enzymes (Molecules 2020, DOI: 10.3390/molecules25061340).

Novel antimicrobials are both difficult to develop and generally underfunded because of a complex web of financial and regulatory disincentives. Hergenrother hopes that he’ll be able to license lolamicin or start a company around it. “We just wanted to get it into the right hands,” he says. But those hands will have a monumental task: further tweaking the compound to make sure that resistance doesn’t develop faster than the antibiotic can become useful.

When the Hergenrother group grew colonies of Escherichia colii, K. pneumoniae, and Enterobacter cloacae in favorable conditions alongside lolamicin, resistance quickly appeared. The bacteria were changing individual amino acids in the LolC and LolE proteins, making it harder for the antibiotic to mess with their ability to transport lipoproteins across the membranes.

Whoever takes on lolamicin will need to do more chemistry work to improve the compound’s ability to bind to those bacteria, says Lynn Silver, a longtime antibiotics developer who now consults for pharmaceutical companies. She reviewed the paper independently and was not involved in the research.

“The rate of resistance is pretty high,” Silver says. “It’s in the range where I worry about whether this will be able to last.”