The drug candidate, called fabimycin, was shown to be potent against over 300 drug-resistant clinical isolates.
Because the bacteria that cause urinary tract infections are becoming more and more resistant to many antibiotics, they are becoming more and more difficult to treat. Researchers report the discovery of a new molecule that suppresses drug-resistant bacteria in lab experiments as well as in mice with pneumonia and urinary tract infections in a study published in ACS Central Science. According to the researchers, the compound fabimycin may one day be used to treat severe bacterial infections in humans.
According to the U.S. Centers for Disease Control and Prevention, gram-negative bacteria are a group of microbes that infect millions of people worldwide, leading to illnesses like pneumonia, urinary tract infections, and bloodstream infections. These bacteria have powerful defense systems, namely tough cell walls that keep the majority of antibiotics out and pumps that effectively remove any antibiotics that do get inside, making them particularly challenging to treat.
The microbes may also mutate to evade multiple drugs. Furthermore, treatments that do work aren’t very specific, leading them to also eradicate beneficial bacteria. Therefore, Paul Hergenrother and colleagues wanted to design a drug that could infiltrate the defenses of gram-negative bacteria and treat infections, while leaving other helpful microbes intact.
The team started with an antibiotic that was active against gram-positive bacteria. They then made a series of structural modifications that they believed would allow it to act against gram-negative strains. One of the modified compounds, named fabimycin, proved potent against more than 300 drug-resistant clinical isolates while remaining relatively inactive toward certain gram-positive pathogens and some typically harmless bacteria that live in or on the human body.
Furthermore, the new molecule reduced the amount of drug-resistant bacteria in mice with pneumonia or urinary tract infections to pre-infection levels or below, performing as well as or better than existing antibiotics at similar doses. The researchers believe that the results show that fabimycin could one day be an effective treatment for stubborn infections.
Reference: “An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with In Vivo Efficacy against Drug-Resistant Gram-Negative Infections” by Erica N. Parker, Brett N. Cain, Behnoush Hajian, Rebecca J. Ulrich, Emily J. Geddes, Sulyman Barkho, Hyang Yeon Lee, John D. Williams, Malik Raynor, Diana Caridha, Angela Zaino, Mrinal Shekhar, Kristen A. Muñoz, Kara M. Rzasa, Emily R. Temple, Diana Hunt, Xiannu Jin, Chau Vuong, Kristina Pannone, Aya M. Kelly, Michael P. Mulligan, Katie K. Lee, Gee W. Lau, Deborah T. Hung and Paul J. Hergenrother, 10 August 2022, ACS Central Science.
The study was funded by the University of Illinois, the National Institutes of Health, the National Science Foundation, the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator, Anita and Josh Bekenstein, Biomedical Advanced Research and Development Authority, Military Infectious Diseases Research Program, and the Roy J. Carver Charitable Trust.