Flightpath Biosciences, Inc., a clinical-stage biotechnology company, has secured an exclusive global license for lolamicin, a groundbreaking antibiotic developed at the University of Illinois Urbana-Champaign that selectively targets gram-negative bacterial pathogens while preserving beneficial gut microbes. The licensing agreement represents a significant advancement in addressing one of medicine's most challenging problems: treating multidrug-resistant gram-negative infections without disrupting the patient's microbiome.
Novel Mechanism Targets Difficult-to-Treat Pathogens
The lolamicin class of antibiotics works by inhibiting the Lol system, a lipoprotein-transport system exclusive to gram-negative bacteria. University of Illinois chemistry professor Paul Hergenrother, whose laboratory developed the compound, explained that his team recognized the Lol system was genetically different in pathogenic versus beneficial microbes, making it a promising target for selective antimicrobial therapy.
"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.
The research team began by examining compounds originally studied by AstraZeneca, then designed structural variations of the Lol inhibitors to enhance their antibacterial properties. In laboratory experiments, lolamicin selectively targeted gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae while showing no detectable effect on gram-positive bacteria.
Exceptional Efficacy Against Multidrug-Resistant Strains
Laboratory testing revealed lolamicin's potent activity against clinical isolates of multidrug-resistant bacteria. At higher doses, the antibiotic killed up to 100% of multidrug-resistant E. coli, K. pneumoniae, and E. cloacae clinical isolates, demonstrating its potential to address some of the most challenging bacterial infections in clinical practice.
Animal model studies further validated the drug's therapeutic potential. When administered orally to mice with drug-resistant infections, lolamicin rescued 100% of mice with septicemia and 70% of mice with pneumonia. These results, published in Nature in 2024, highlight the compound's ability to treat life-threatening systemic infections.
Microbiome Preservation Sets New Standard
Perhaps most significantly, detailed analysis showed that lolamicin had no deleterious effect on the gut microbiome of treated mice, contrasting sharply with clinically approved antibiotics that killed many beneficial bacteria and disturbed the gut microbiome. This microbiome-sparing property addresses a critical limitation of current antibiotic therapies, which often cause collateral damage to the patient's beneficial microbial communities.
The preservation of gut microbiome integrity could have implications beyond infection treatment. Hergenrother noted that pathogenic E. coli and K. pneumoniae are implicated in various conditions beyond septicemia and pneumonia, including certain inflammatory conditions and some cancers.
"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.
Development Timeline and Strategic Partnership
The lolamicin platform remains in early-stage development, requiring additional preclinical studies to demonstrate safety and efficacy before filing an Investigational New Drug application with the FDA. Matt Tindall, executive chairman and CEO of Flightpath Biosciences, indicated the company aims to initiate human clinical trials as early as 2026.
"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."
Hergenrother expressed confidence in the partnership, citing Flightpath's operational track record and stability. "We were attracted to Flightpath as a partner because of its past operational and development successes and its stability as a company," he said. "Flightpath has the capabilities and resources to advance this exciting new technology for patients."
The University of Illinois team continues developing derivatives of lolamicin, potentially expanding the therapeutic options within this novel antibiotic class. The licensing agreement positions Flightpath to advance this microbiome-sparing approach through clinical development, potentially offering new hope for patients with difficult-to-treat gram-negative bacterial infections.
