Small-molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere01524-18
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number3
DOIs
Publication statusPublished - 03-2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Tomich, A. D., Klontz, E. H., Deredge, D., Barnard, J. P., McElheny, C. L., Eshbach, M. L., Weisz, O. A., Wintrode, P., Doi, Y., Sundberg, E. J., & Sluis-Cremer, N. (2019). Small-molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens. Antimicrobial agents and chemotherapy, 63(3), [e01524-18]. https://doi.org/10.1128/AAC.01524-18