Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 615.19 Pharmaceutical chemistry

Thông tin xuất bản: Bethesda, Md. : Oak Ridge, Tenn. : National Institutes of Health (U.S.) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019

Mô tả vật lý: Size: Article No. e01524-18 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 260117

 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 <
 em>
 Escherichia coli<
 /em>
 , including multidrug-resistant strains. However, many other Gram-negative pathogens, including the ?priority pathogens? <
 em>
 Klebsiella pneumoniae<
 /em>
  and <
 em>
 Pseudomonas aeruginosa<
 /em>
 , 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.
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