CHAMPAIGN, Ill. — Flightpath Biosciences, Inc., a clinical stage biotechnology company focused on the development of precision therapeutics targeting bacterial pathogens, has licensed a class of antibiotics developed at the University of Illinois Urbana-Champaign. The original antibiotic agent, lolamicin, effectively treated bacterial infections in animal models of disease — without wiping out beneficial microbes in the gut. The Illinois team is continuing to develop derivatives of lolamicin.
This class of drugs is notable for sparing healthy microbes but also for targeting pathogenic gram-negative bacteria, the most difficult bacterial infections to treat, said U. of I. chemistry professor Paul Hergenrother, whose lab produced lolamicin and its derivatives.
Hergenrother’s team started its antibiotic-development process by focusing on a suite of compounds originally studied by pharmaceutical company AstraZeneca. These compounds were found to inhibit the Lol system, a lipoprotein-transport system exclusive to gram-negative bacteria.
“Although these progenitor compounds were not effective against bacteria, we recognized that the Lol system was genetically different in pathogenic versus beneficial microbes, making them promising candidates for further exploration,” Hergenrother said.
In a series of experiments, Hergenrother’s team designed structural variations of the Lol inhibitors and evaluated their potential to kill gram-negative and gram-positive bacteria in cell culture. In the experiments, lolamicin selectively targeted some “laboratory strains of gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae,” the researchers found. Lolamicin had no detectable effect on gram-positive bacteria in cell culture. At higher doses, lolamicin killed up to 100% of multidrug-resistant E. coli, K. pneumoniae and E. cloacae clinical isolates.
Further tests demonstrated the drug’s efficacy in animal models of infection. When given orally to mice with drug-resistant septicemia or pneumonia, lolamicin rescued 100% of the mice with septicemia and 70% of the mice with pneumonia, the team reported.
Importantly, detailed analysis showed that lolamicin had no deleterious effect on the gut microbiome of mice, whereas clinically approved antibiotics killed many of these “good” bacteria, disturbing the gut microbiome. These results were published in the journal Nature in 2024.
Pathogenic E. coli and K. pneumoniae are implicated in a host of infections and diseases beyond septicemia and pneumonia, including certain inflammatory conditions and some cancers, Hergenrother said.
“So, we are hoping these new antibiotics can be life-saving drugs for patients with difficult-to-treat infections, but they also could be useful for other indications,” he said.
The lolamicin class of drugs is still early in the drug-development process. Additional preclinical studies must be conducted to demonstrate the lead drug candidate’s safety and efficacy, followed by an “Investigational New Drug” application to the Food and Drug Administration. If all goes well, the company aims to start human clinical trials perhaps as early as 2026, said Matt Tindall, the executive chairman and CEO of Flightpath Biosciences, which has obtained an exclusive global license for all uses of the lolamicin platform.
“The novel mechanism of action and resulting targeted drug candidates are potential game-changers in the treatment of infection-driven diseases, preserving, rather than undermining, an intact healthy microbiome and immune system,” Tindall said. “The lolamicin technology platform is a perfect complement to Flightpath’s strategy of eliminating causal or exacerbating pathogens while sparing the patient’s microbiome.”
“We were attracted to Flightpath as a partner because of its past operational and development successes and its stability as a company,” Hergenrother said. “Flightpath has the capabilities and resources to advance this exciting new technology for patients.”
Hergenrother is a deputy director of the Cancer Center at Illinois and an affiliate of the Carle Illinois College of Medicine and the Carl R. Woese Institute for Genomic Biology at the U. of I.
Editor’s notes:
To reach Paul Hergenrother, email hergenro@illinois.edu.
To reach Matthew Tindall, email matt@flighpath.bio.
The paper “A Gram-negative-selective antibiotic spares the gut microbiome” is available online.
DOI: 0.1038/s41586-024-07502-0
