6C3U

Crystal structure of Klebsiella pneumoniae fosfomycin resistance protein (FosAKP) with inhibitor (ANY2) bound

Summary for 6C3U

• Entry DOI: 10.2210/pdb6c3u/pdb
• Related: 5V3D 5V91 5WEW
• Descriptor: FosA family fosfomycin resistance glutathione transferase, MANGANESE (II) ION, 3-bromo-6-(4-nitro-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-2(1H)-one, ... (5 entities in total)
• Functional Keywords: fosfomycin, fosa, fosakp, glutathione s-transferase, any2, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 4
• Total formula weight: 66849.55

Authors

Klontz, E.H.,Sundberg, E.J. (deposition date: 2018-01-10, release date: 2018-12-26, 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 (1.85 Å)