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

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 againstEscherichia 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 fosAgene, 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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1497177
Resource Type:
Journal Article
Journal Name:
Antimicrobial Agents and Chemotherapy
Additional Journal Information:
Journal Volume: 63; Journal Issue: 3; Journal ID: ISSN 0066-4804
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

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., and Sluis-Cremer, Nicolas. Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens. United States: N. p., 2019. Web. doi:10.1128/AAC.01524-18.
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. Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens. United States. doi:10.1128/AAC.01524-18.
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., and Sluis-Cremer, Nicolas. Mon . "Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens". United States. doi:10.1128/AAC.01524-18.
@article{osti_1497177,
title = {Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens},
author = {Tomich, Adam D. and Klontz, Erik H. and Deredge, Daniel and Barnard, John P. and McElheny, Christi L. and Eshbach, Megan L. and Weisz, Ora A. and Wintrode, Patrick and Doi, Yohei and Sundberg, Eric J. and Sluis-Cremer, Nicolas},
abstractNote = {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 againstEscherichia 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 fosAgene, which directs expression of a metal-dependent glutathioneS-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.},
doi = {10.1128/AAC.01524-18},
journal = {Antimicrobial Agents and Chemotherapy},
issn = {0066-4804},
number = 3,
volume = 63,
place = {United States},
year = {2019},
month = {1}
}