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Discovery of natural compound may help fend off antibiotic resistance of hard-to-treat infections

by Aug. 19, 2020, 12:00 PM

The Vanderbilt Laboratory for Biosynthetic Studies, led by Brian Bachmann, professor of chemistry, has discovered a naturally occurring compound that is resilient to antibiotic resistance because of its rare properties. Antibiotic resistance, the ability of bacteria to evade antibiotic treatment, has been identified by the Centers for Disease Control and Prevention as one of the largest public health challenges, affecting at least 2.8 million people in the U.S. each year.

Brian Bachmann
Brian Bachmann (Vanderbilt)

The article announcing this discovery, “A bifunctional nitrone conjugated secondary metabolite targeting the ribosome,” was posted online in the Journal of the American Chemical Society on July 24.

Emilianne Limbrick, a former graduate student on Bachmann’s team and current assistant professor of chemistry at Mercer University, discovered an exotic chemical fusion of two antibiotics being produced within the soil microorganism Micromonospora. Many successful antibiotics have been discovered from soil microbes. But typically, successful discovery programs identify a single antibiotic targeting a single drug target being produced within a microorganism, which can be used to treat bacterial infections after rigorous clinical testing. In this case, an antibiotic inhibiting two different bacterial targets was discovered. That means the likelihood of the bacteria being able to develop a resistance to the functionalities of two antibiotics instead of one is far less likely, making this compound significantly more potent and durable in fighting drug-resistant infection.

“This molecule represents an entirely new blueprint for a drug that can treat multiple life-threatening and drug-resistant bacterial infections, with a unique mode of evading resistance,” said Bachmann, who is also co-director of the Biochemistry and Chemical Biology Program.

Following Bachmann’s discovery of the compound, Daniel Wilson, a professor in the Department of Chemistry at the University of Hamburg, took a snapshot of the antibiotic at work in atomic resolution. This level of visualization has been made available only recently, and it enabled the researchers to show how mutations confer resistance to just one—but not both—of the antibiotics.

This compound has the potential to effectively treat bacterial infections resistant to multiple drugs, including Clostridioides difficile (C. diff), which causes inflammation of the colon and sometimes death, and Staphylococcus aureus (Staph) infections, which are the result of a highly resistant bacteria. Bachmann is working with the Center for Technology Transfer and Commercialization to explore development for clinical use.

Funding for this research was provided by NIH/NIAD grant 1R01AI140400, the Vanderbilt Institute of Chemical Biology, the D. Stanley and Ann T. Tarbell Endowment Fund and grant 12GRNT11920011 from the American Heart Association. Scanning electron microscopy was performed at the VUMC Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637 and EY08126).