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Antimicrob Agents Chemother. 2019 Feb 26;63(3). pii: e01524-18. doi: 10.1128/AAC.01524-18. Print 2019 Mar.

Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens.

Author information

1
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
3
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
4
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
5
Division of Renal-Electrolyte, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
6
Center for Innovative Antimicrobial Therapy, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
7
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA ESundberg@ihv.umaryland.edu nps2@pitt.edu.
8
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
9
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ESundberg@ihv.umaryland.edu nps2@pitt.edu.
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Contributed equally

Abstract

The spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active against Escherichia coli, including multidrug-resistant strains. However, many other Gram-negative pathogens, including the "priority pathogens" Klebsiella pneumoniae and Pseudomonas aeruginosa, are inherently resistant to FOM due to the chromosomal fosA gene, which directs expression of a metal-dependent glutathione S-transferase (FosA) that metabolizes FOM. In this study, we describe the discovery and biochemical and structural characterization of ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one), a small-molecule active-site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains.

KEYWORDS:

FosA; Gram negative; fosfomycin

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