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 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.
- Authors:
-
- 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)
- 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
- Grant/Contract Number:
- R21AI123747; T32DK061296; TL1TR001858; T32AI095190
- Resource Type:
- Accepted Manuscript
- 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
- Subject:
- 60 APPLIED LIFE SCIENCES; FosA; Gram negative; fosfomycin
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. https://doi.org/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. https://doi.org/10.1128/aac.01524-18. https://www.osti.gov/servlets/purl/1497177.
@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 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.},
doi = {10.1128/aac.01524-18},
journal = {Antimicrobial Agents and Chemotherapy},
number = 3,
volume = 63,
place = {United States},
year = {Mon Jan 14 00:00:00 EST 2019},
month = {Mon Jan 14 00:00:00 EST 2019}
}
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Works referenced in this record:
Biological Costs and Mechanisms of Fosfomycin Resistance in Escherichia coli
journal, August 2003
- Nilsson, A. I.; Berg, O. G.; Aspevall, O.
- Antimicrobial Agents and Chemotherapy, Vol. 47, Issue 9
Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation
journal, February 2010
- Michalopoulos, A.; Virtzili, S.; Rafailidis, P.
- Clinical Microbiology and Infection, Vol. 16, Issue 2
The Mechanism of Action of Fosfomycin (Phosphonomycin)
journal, May 1974
- Kahan, Frederick M.; Kahan, Jean S.; Cassidy, Patrick J.
- Annals of the New York Academy of Sciences, Vol. 235, Issue 1 Mode of Actio
Characterization of a Cys115 to Asp Substitution in the Escherichia coli Cell Wall Biosynthetic Enzyme UDP-GlcNAc Enolpyruvyl Transferase (MurA) That Confers Resistance to Inactivation by the Antibiotic Fosfomycin †
journal, January 1996
- Kim, Dennis H.; Lees, Watson J.; Kempsell, Karen E.
- Biochemistry, Vol. 35, Issue 15
Fosfomycin: Resurgence of an old companion
journal, May 2016
- Sastry, Sangeeta; Doi, Yohei
- Journal of Infection and Chemotherapy, Vol. 22, Issue 5
Fosfomycin Resistance Protein (FosA) Is a Manganese Metalloglutathione Transferase Related to Glyoxalase I and the Extradiol Dioxygenases †
journal, March 1997
- Bernat, Bryan A.; Laughlin, L. Timothy; Armstrong, Richard N.
- Biochemistry, Vol. 36, Issue 11
Functional Consequence of Covalent Reaction of Phosphoenolpyruvate with UDP- N -acetylglucosamine 1-Carboxyvinyltransferase (MurA)
journal, February 2012
- Zhu, Jin-Yi; Yang, Yan; Han, Huijong
- Journal of Biological Chemistry, Vol. 287, Issue 16
Phosphonoformate: A Minimal Transition State Analogue Inhibitor of the Fosfomycin Resistance Protein, FosA † , ‡
journal, November 2004
- Rigsby, Rachel E.; Rife, Chris L.; Fillgrove, Kerry L.
- Biochemistry, Vol. 43, Issue 43
Fosfomycin Resistance in Escherichia coli , Pennsylvania, USA
journal, November 2015
- Alrowais, Hind; McElheny, Christi L.; Spychala, Caressa N.
- Emerging Infectious Diseases, Vol. 21, Issue 11
Modeling of the Bacterial Growth Curve
journal, January 1990
- Zwietering, M. H.; Jongenburger, I.; Rombouts, F. M.
- Applied and Environmental Microbiology, Vol. 56, Issue 6
Functional Analysis of Active Site Residues of the Fosfomycin Resistance Enzyme FosA from Pseudomonas aeruginosa
journal, March 2005
- Beharry, Zanna; Palzkill, Timothy
- Journal of Biological Chemistry, Vol. 280, Issue 18
ESKAPEing the labyrinth of antibacterial discovery
journal, July 2015
- Tommasi, Ruben; Brown, Dean G.; Walkup, Grant K.
- Nature Reviews Drug Discovery, Vol. 14, Issue 8
Intravenous fosfomycin—back to the future. Systematic review and meta-analysis of the clinical literature
journal, June 2017
- Grabein, B.; Graninger, W.; Rodríguez Baño, J.
- Clinical Microbiology and Infection, Vol. 23, Issue 6
Predictive compound accumulation rules yield a broad-spectrum antibiotic
journal, May 2017
- Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.
- Nature, Vol. 545, Issue 7654
Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal fosA Gene
journal, August 2017
- Ito, Ryota; Mustapha, Mustapha M.; Tomich, Adam D.
- mBio, Vol. 8, Issue 4
The Utility of Hydrogen/Deuterium Exchange Mass Spectrometry in Biopharmaceutical Comparability Studies
journal, June 2011
- Houde, Damian; Berkowitz, Steven A.; Engen, John R.
- Journal of Pharmaceutical Sciences, Vol. 100, Issue 6
Inhibition of Fosfomycin Resistance Protein FosA by Phosphonoformate (Foscarnet) in Multidrug-Resistant Gram-Negative Pathogens
journal, October 2017
- Ito, Ryota; Tomich, Adam D.; McElheny, Christi L.
- Antimicrobial Agents and Chemotherapy, Vol. 61, Issue 12
Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli
journal, September 2017
- Klontz, Erik H.; Tomich, Adam D.; Günther, Sebastian
- Antimicrobial Agents and Chemotherapy, Vol. 61, Issue 11
Fosfomycin: Mechanism and Resistance
journal, January 2017
- Silver, Lynn L.
- Cold Spring Harbor Perspectives in Medicine, Vol. 7, Issue 2