美国纽约大学医学院Evgeny Nudler课题组研制了针对抗生素耐药和耐受细菌的H2S生物发生抑制剂。相关论文于2021年6月11日发表在《科学》杂志上。

在本研究中，研究人员揭示了一种针对细菌硫化氢 (H2S)介导防御体系的有效抗菌策略。研究人员发现胱硫醚 γ-裂解酶 (CSE)介导了两种主要人类病原体-金黄色葡萄球菌和铜绿假单胞菌中H2S的生成，并发现了抑制细菌CSE的小分子。这些抑制剂在体外和小鼠感染模型中增强了杀菌抗生素对这两种病原体的作用。

CSE 抑制剂还抑制细菌耐受性，破坏生物膜的形成，并显著减少抗生素治疗后持久存活细菌的数量。该研究结果表明细菌H2S是多功能防御因子以及靶向CSE的抑制剂可作为多功能抗生素的增强剂。

据介绍，对所有临床抗生素耐药菌株的出现急需研发新的疗法。

附：英文原文

Title: Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance

Author: Konstantin Shatalin, Ashok Nuthanakanti, Abhishek Kaushik, Dmitry Shishov, Alla Peselis, Ilya Shamovsky, Bibhusita Pani, Mirna Lechpammer, Nikita Vasilyev, Elena Shatalina, Dmitri Rebatchouk, Alexander Mironov, Peter Fedichev, Alexander Serganov, Evgeny Nudler

Issue&Volume: 2021/06/11

Abstract: Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)–mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

DOI: 10.1126/science.abd8377

Source: https://science.sciencemag.org/content/372/6547/1169