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.

Autor:	Parker EN; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Cain BN; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Hajian B; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Ulrich RJ; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Geddes EJ; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Barkho S; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Lee HY; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Williams JD; Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States., Raynor M; Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States., Caridha D; Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States., Zaino A; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Shekhar M; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Muñoz KA; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Rzasa KM; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Temple ER; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Hunt D; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.; Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02115, United States., Jin X; Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States., Vuong C; Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States., Pannone K; Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States., Kelly AM; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Mulligan MP; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Lee KK; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Lau GW; Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., Hung DT; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.; Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02115, United States., Hergenrother PJ; Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2022 Aug 24; Vol. 8 (8), pp. 1145-1158. Date of Electronic Publication: 2022 Aug 10.
DOI:	10.1021/acscentsci.2c00598
Abstrakt:	Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. Notably, FabI inhibitors have advanced to clinical trials for Staphylococcus aureus infections but not for infections caused by Gram-negative bacteria. Here, we synthesize a suite of FabI inhibitors whose structures fit permeation rules for Gram-negative bacteria and leverage activity against a challenging panel of Gram-negative clinical isolates as a filter for advancement. The compound to emerge, called fabimycin, has impressive activity against >200 clinical isolates of Escherichia coli , Klebsiella pneumoniae , and Acinetobacter baumannii , 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. Competing Interests: The authors declare the following competing financial interest(s): The University of Illinois and the Broad Institute have filed patents on some compounds described herein. (© 2022 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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