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(University of Illinois Urbana-Champaign), Brett N. Cain(University of Illinois Urbana-Champaign), Behnoush Hajian(Broad Institute), Rebecca J. Ulrich(University of Illinois Urbana-Champaign), Emily J. Geddes(University of Illinois Urbana-Champaign), Sulyman Barkho(Broad Institute), Hyang Yeon Lee(University of Illinois Urbana-Champaign), John D. Williams(Walter Reed Army Institute of Research), Malik Raynor(Walter Reed Army Institute of Research), Diana Caridha(Walter Reed Army Institute of Research), Angela M. Zaino(Broad Institute), Mrinal Shekhar(Broad Institute), Kristen A. Muñoz(University of Illinois Urbana-Champaign), Kara M. Rzasa(Broad Institute), Emily R. Temple(Broad Institute), Diana K. Hunt(Broad Institute), Xiannu Jin(Walter Reed Army Institute of Research), Chau Vuong(Walter Reed Army Institute of Research), Kristina Pannone(Walter Reed Army Institute of Research), Aya M. Kelly(University of Illinois Urbana-Champaign), Michael P. Mulligan(University of Illinois Urbana-Champaign), Katie K. Lee(Broad Institute), Gee W. Lau(University of Illinois Urbana-Champaign), Deborah T. Hung(Broad Institute), Paul J. Hergenrother(University of Illinois Urbana-Champaign)
Cited by 73Open Access
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.
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