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

Tomich, Adam D.; Klontz, Erik H.; Deredge, Daniel; Barnard, John P.; McElheny, Christi L.; Eshbach, Megan L.; Weisz, Ora A.; Wintrode, Patrick; Doi, Yohei; Sundberg, Eric J.; Sluis-Cremer, Nicolas

doi:10.1128/aac.01524-18

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

Journal Article · Sun Jan 13 23:00:00 EST 2019 · Antimicrobial Agents and Chemotherapy

DOI:https://doi.org/10.1128/aac.01524-18· OSTI ID:1497177

Tomich, Adam D. ^[1]; Klontz, Erik H. ^[2]; Deredge, Daniel ^[2]; Barnard, John P. ^[1]; McElheny, Christi L. ^[1]; Eshbach, Megan L. ^[1]; Weisz, Ora A. ^[1]; Wintrode, Patrick ^[3]; Doi, Yohei ^[1]; Sundberg, Eric J. ^[2]; Sluis-Cremer, Nicolas ^[1]

Univ. of Pittsburgh School of Medicine, PA (United States)
Univ. of Maryland School of Medicine, Baltimore, MD (United States)
Univ. of Maryland School of Pharmacy, Baltimore, MD (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1497177

Journal Information:: Antimicrobial Agents and Chemotherapy, Journal Name: Antimicrobial Agents and Chemotherapy Journal Issue: 3 Vol. 63; ISSN 0066-4804

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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60 APPLIED LIFE SCIENCES
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