TY - JOUR
T1 - Small-molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens
AU - Tomich, Adam D.
AU - Klontz, Erik H.
AU - Deredge, Daniel
AU - Barnard, John P.
AU - McElheny, Christi L.
AU - Eshbach, Megan L.
AU - Weisz, Ora A.
AU - Wintrode, Patrick
AU - Doi, Yohei
AU - Sundberg, Eric J.
AU - Sluis-Cremer, Nicolas
N1 - Funding Information:
This study was supported by a research grant from the National Institutes of Health (grant number R21AI123747). M.L.E. was supported by grants T32DK061296 and TL1TR001858, and E.H.K. was supported by T32AI095190.
Publisher Copyright:
Copyright © 2019 American Society for Microbiology. All Rights Reserved.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
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U2 - 10.1128/AAC.01524-18
DO - 10.1128/AAC.01524-18
M3 - Article
C2 - 30642934
AN - SCOPUS:85062260826
SN - 0066-4804
VL - 63
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 3
M1 - e01524-18
ER -