Small-molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens

Adam D. Tomich, Erik H. Klontz, Daniel Deredge, John P. Barnard, Christi L. McElheny, Megan L. Eshbach, Ora A. Weisz, Patrick Wintrode, Yohei Doi, Eric J. Sundberg, Nicolas Sluis-Cremer

研究成果: Article査読

6 被引用数 (Scopus)

抄録

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. 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.

本文言語English
論文番号e01524-18
ジャーナルAntimicrobial agents and chemotherapy
63
3
DOI
出版ステータスPublished - 03-2019
外部発表はい

All Science Journal Classification (ASJC) codes

  • 薬理学
  • 薬理学(医学)
  • 感染症

フィンガープリント

「Small-molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル