5WEP

Crystal structure of fosfomycin resistance protein FosA3 with inhibitor (ANY1) bound

Summary for 5WEP

• Entry DOI: 10.2210/pdb5wep/pdb
• Related: 5VB0
• Descriptor: FosA3, 6,6'-(4-nitro-1H-pyrazole-3,5-diyl)bis(3-bromopyrazolo[1,5-a]pyrimidin-2(1H)-one), ZINC ION (3 entities in total)
• Functional Keywords: fosfomycin, fosa, fosa3, glutathione s-transferase, any1, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 33697.39

Authors

Klontz, E.H.,Sundberg, E.J. (deposition date: 2017-07-10, release date: 2018-07-18, Last modification date: 2023-10-04)

Primary citation

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.
Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens.
Antimicrob. Agents Chemother., 63:-, 2019

PubMed 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 , including multidrug-resistant strains. However, many other Gram-negative pathogens, including the "priority pathogens" and , are inherently resistant to FOM due to the chromosomal gene, which directs expression of a metal-dependent glutathione -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.

PubMed: 30642934
DOI: 10.1128/AAC.01524-18

Experimental method

X-RAY DIFFRACTION (3.502 Å)