An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with <i>In Vivo</i> Efficacy against Drug-Resistant Gram-Negative Infections
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 M. Zaino, Mrinal Shekhar, Kristen A. Muñoz, Kara M. Rzasa, Emily R. Temple, Diana K. Hunt, Xiannu Jin, Chau Vuong, Kristina Pannone, Aya M. Kelly, Michael P. Mulligan, Katie K. Lee, Gee W. Lau, Deborah T. Hung, Paul J. Hergenrother
Abstract
, and does not kill commensal bacteria. X-ray structures of fabimycin in complex with FabI provide molecular insights into the inhibition. Fabimycin demonstrates activity in multiple mouse models of infection caused by Gram-negative bacteria, including a challenging urinary tract infection model. Fabimycin has translational promise, and its discovery provides additional evidence that antibiotics can be systematically modified to accumulate in Gram-negative bacteria and kill these problematic pathogens.