Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2019 Feb 26;63(3). doi: 10.1128/AAC.01524-18. Print 2019 Mar.
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.
多药耐药或广泛耐药革兰氏阴性菌的传播是一个严重的公共卫生问题。可用于治疗多药耐药感染的新抗生素数量太少，而抗生素耐药性的增加速度超过了药物开发进程。这从根本上威胁到我们治疗常见传染病的能力。磷霉素（FOM）在人类中的安全性已有充分的记录，并且对多种革兰氏阴性菌具有高度活性，包括多药耐药株。然而，许多其他革兰氏阴性病原体，包括“优先病原体”和，由于染色体基因，对 FOM 具有固有耐药性，该基因指导表达一种金属依赖性谷胱甘肽 - 转移酶（FosA），该酶代谢 FOM。在这项研究中，我们描述了 ANY1（3-溴-6-[3-（3-溴-2-氧代-1H-吡唑并[1,5-a]嘧啶-6-基）-4-硝基-1H-吡唑并[1,5-a]嘧啶-5-基]-1H-吡唑并[1,5-a]嘧啶-2-酮）的发现以及其对 FosA 的生化和结构特征，ANY1 是 FosA 的一种小分子活性位点抑制剂。重要的是，ANY1 增强了 FOM 在代表性革兰氏阴性病原体中的活性。总的来说，我们的研究概述了一种将 FOM 活性扩展到更广泛的革兰氏阴性病原体（包括多药耐药株）的新策略。
