@article{b053e368cab4467b8922d57abcfe6b5b,
title = "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",
abstract = "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.",
author = "Parker, {Erica N.} and Cain, {Brett N.} and Behnoush Hajian and Ulrich, {Rebecca J.} and Geddes, {Emily J.} and Sulyman Barkho and Lee, {Hyang Yeon} and Williams, {John D.} and Malik Raynor and Diana Caridha and Angela Zaino and Mrinal Shekhar and Mu{\~n}oz, {Kristen A.} and Rzasa, {Kara M.} and Temple, {Emily R.} and Diana Hunt and Xiannu Jin and Chau Vuong and Kristina Pannone and Kelly, {Aya M.} and Mulligan, {Michael P.} and Lee, {Katie K.} and Lau, {Gee W.} and Hung, {Deborah T.} and Hergenrother, {Paul J.}",
note = "Funding Information: This work was supported by the University of Illinois and the NIH (AI136773 to P.J.H. and G.W.L.). K.A.M. and M.P.M. are members of the NIH Chemistry-Biology Interface Training Grant (T32-GM136629). R.J.U. is supported by an NIH Ruth Kirschstein Award (F31AI161953) and was an NSF predoctoral fellow. This work utilized NIAID{\textquoteright}s suite of preclinical services for in vitro and in vivo assessment (Contract Numbers HHSN272201700020I_75N93021F00001 HHSN272201700020I_75N93021F00002, and 75N93019D00022_75N93020F00001). The Collaborative Hub for Early Antibiotic Discovery (CHEAD) is grateful for financial support from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X). This work was supported by a gift from Anita and Josh Bekenstein and by funding provided under Cooperative Agreement #IDSEP160030-01-00 from Biomedical Advanced Research and Development Authority (BARDA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of The Assistant Secretary for Preparedness and Response. This project has been funded in part by federal funds from the Military Infectious Disease Research Program Proposals MI210200 and MI220020. We thank L. Li (Metabolomics Center, Roy J. Carver Biotechnology Center, UIUC) for LC-MS/MS analysis. We thank Dean Olson, Lingyang Zhu, and N. Duay at the School of Chemical Sciences NMR Laboratory at UIUC for NMR services. The Bruker 500 MHz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, Iowa Funding Information: This work was supported by the University of Illinois and the NIH (AI136773 to P.J.H. and G.W.L.). K.A.M. and M.P.M. are members of the NIH Chemistry–Biology Interface Training Grant (T32-GM136629). R.J.U. is supported by an NIH Ruth Kirschstein Award (F31AI161953) and was an NSF predoctoral fellow. This work utilized NIAID{\textquoteright}s suite of preclinical services for in vitro and in vivo assessment (Contract Numbers HHSN272201700020I_75N93021F00001, HHSN272201700020I_75N93021F00002, and 75N93019D00022_75N93020F00001). The Collaborative Hub for Early Antibiotic Discovery (CHEAD) is grateful for financial support from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X). This work was supported by a gift from Anita and Josh Bekenstein and by funding provided under Cooperative Agreement #IDSEP160030-01-00 from Biomedical Advanced Research and Development Authority (BARDA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of The Assistant Secretary for Preparedness and Response. This project has been funded in part by federal funds from the Military Infectious Disease Research Program Proposals MI210200 and MI220020. We thank L. Li (Metabolomics Center, Roy J. Carver Biotechnology Center, UIUC) for LC-MS/MS analysis. We thank Dean Olson, Lingyang Zhu, and N. Duay at the School of Chemical Sciences NMR Laboratory at UIUC for NMR services. The Bruker 500 MHz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, Iowa. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",
year = "2022",
month = aug,
day = "24",
doi = "10.1021/acscentsci.2c00598",
language = "English (US)",
volume = "8",
pages = "1145--1158",
journal = "ACS Central Science",
issn = "2374-7943",
publisher = "American Chemical Society",
number = "8",
}