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Rox, a Rifamycin Resistance Enzyme with an Unprecedented Mechanism of Action
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2018-02-01 , DOI: 10.1016/j.chembiol.2018.01.009
Kalinka Koteva , Georgina Cox , Jayne K. Kelso , Matthew D. Surette , Haley L. Zubyk , Linda Ejim , Peter Stogios , Alexei Savchenko , Dan Sørensen , Gerard D. Wright

Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducibleroxgene fromStreptomyces venezuelae, which encodes a class A flavoprotein monooxygenase that inactivates a broad range of rifamycin antibiotics. Our findings describe a mechanism of rifamycin inactivation initiated by monooxygenation of the 2-position of the naphthyl group, which subsequently results in ring opening and linearization of the antibiotic. The result is an antibiotic that no longer adopts the basket-like structure essential for binding to the RNA exit tunnel of the target RpoB, thereby providing the molecular logic of resistance. This unique mechanism of enzymatic inactivation underpins the broad spectrum of rifamycin resistance mediated by Rox enzymes and presents a new antibiotic resistance mechanism not yet seen in microbial antibiotic detoxification.

中文翻译:

Rox,一种具有前所未有的作用机制的利福霉素抗性酶

利福霉素单加氧酶(Rox)存在于多种环境细菌中,并与临床使用的抗生素利福平的分解有关。在这里,我们报告了委内瑞拉链霉菌的药物诱导型大约基因的结构和功能,该基因编码可灭活广泛的利福霉素抗生素的A类黄素单加氧酶。我们的发现描述了由萘基的2位单加氧引起的利福霉素失活的机制,随后导致抗生素的开环和线性化。结果是抗生素不再采用与靶标RpoB的RNA出口通道结合所必需的篮状结构,从而提供了抗药性的分子逻辑。
更新日期:2018-04-19
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