Inhibitors of bacterial H<sub>2</sub>S biogenesis targeting antibiotic resistance and tolerance

doi:10.1126/science.abd8377

GSTDTAP > 气候变化

DOI	10.1126/science.abd8377
	Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance
	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
	2021-06-11
发表期刊	Science
出版年	2021
英文摘要	Persister cells, which are found in abundance in biofilms, adopt a quiescent state and survive antimicrobial treatments, seeding disease recurrence and incubating new resistance mutations. Building on work implicating the reactive small-molecule hydrogen sulfide in bacterial defense against antibiotics, Shatalin et al. conducted a structure-based screen for inhibitors of a bacterial hydrogen sulfide–producing enzyme and found a group of inhibitors that act through an allosteric mechanism (see the Perspective by Mah). These inhibitors potentiated bactericidal antibiotics in vitro and in mouse infection models. They also suppressed persister bacteria and disrupted biofilm formation. This strategy of taking out persister cells may be promising for treating recalcitrant infections and holding the line against drug-resistant bacteria. Science , abd8377, this issue p. [1169][1]; see also abj3062, p. [1153][2] 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. [1]: /lookup/doi/10.1126/science.abd8377 [2]: /lookup/doi/10.1126/science.abj3062
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/329908
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Konstantin Shatalin,Ashok Nuthanakanti,Abhishek Kaushik,et al. Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance[J]. Science,2021.
APA	Konstantin Shatalin.,Ashok Nuthanakanti.,Abhishek Kaushik.,Dmitry Shishov.,Alla Peselis.,...&Evgeny Nudler.(2021).Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance.Science.
MLA	Konstantin Shatalin,et al."Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance".Science (2021).