Dr. Hergenrother joins us in this episode to discuss his groundbreaking work on developing antibiotics for challenging Gram-negative bacterial infections. He delves into the difficulties of creating drugs that can effectively bypass the formidable outer membrane and efflux pumps of Gram-negative pathogens to reach biological targets.

A key point in our conversation revolves around the enzyme FabI - an enzyme that catalyzes the rate-determining step in bacterial fatty acid biosynthesis. While FabI inhibitors have been advanced to clinical trials for Staphylococcus aureus infections, Dr. Hergenrother and his team focus on utilizing them against Gram-negative bacteria.

The discussion leads us to fabimycin, a promising compound resulting from synthesizing a suite of FabI inhibitors in accordance with permeation rules for Gram-negative bacteria. Fabimycin shows potent activity against more than 200 clinical isolates of E. coli, K. pneumoniae, and A. baumannii without affecting commensal bacteria.

We discuss the x-ray structures of fabimycin in complex with FabI, providing molecular insights into the inhibition process. Furthermore, we explore how fabimycin shows promise in various mouse models of Gram-negative bacterial infections, including a challenging urinary tract infection model.

The conversation concludes with Dr. Hergenrother emphasizing the translational potential of fabimycin and the broader implications of his team's approach. This includes the assertion that systematic modification of antibiotics can lead to the development of effective treatments against Gram-negative bacteria.

Keywords: Gram-Negative Bacteria, Antibiotics, FabI Inhibitors, Fabimycin, Drug Development, Bacterial Infections, Staphylococcus aureus, E. coli, K. pneumoniae, A. baumannii.

Iterative Approach Guides Discovery of FabI Inhibitor Fabimycin, Late-Stage Antibiotic Candidate w/ In Vivo Efficacy against Drug-Resistant Gram-Negative Infections doi.org/10.1021/acscentsci.2c00598