5wep
Crystal structure of fosfomycin resistance protein FosA3 with inhibitor (ANY1) bound
Structural highlights
FunctionPublication Abstract from PubMedThe 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 chromosomally-encoded 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 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 (ANY1), 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. Small molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens.,Tomich AD, Klontz EH, Deredge D, Barnard JP, McElheny CL, Eshbach ML, Weisz OA, Wintrode P, Doi Y, Sundberg EJ, Sluis-Cremer N Antimicrob Agents Chemother. 2019 Jan 14. pii: AAC.01524-18. doi:, 10.1128/AAC.01524-18. PMID:30642934[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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