新型抗艰难梭菌化合物 LFF571 的作用机制和降低敏感性的机制。
Mechanism of action of and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571.
机构信息
Novartis Institutes for Biomedical Research, Infectious Disease Area, Emeryville, California, USA.
出版信息
Antimicrob Agents Chemother. 2012 Aug;56(8):4463-5. doi: 10.1128/AAC.06354-11. Epub 2012 May 29.
Abstract
LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10(-11) to 1.2 × 10(-9). Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.
摘要
LFF571 是一种新型半合成噻唑肽类抗生素，对革兰氏阳性菌有很强的抑制作用。我们的研究表明，LFF571 对艰难梭菌的抗菌活性是由于其抑制了翻译过程。用 LFF571 进行选择压力下艰难梭菌的一步突变，其对 LFF571 的敏感性降低，突变频率为<4.5×10(-11) 到 1.2×10(-9)。测序结果表明在延伸因子 Tu 的噻唑肽结合口袋中存在 G260E 取代。重要的是，这种突变并没有赋予交叉耐药性到临床上使用的抗生素。这些结果支持了 LFF571 作为治疗艰难梭菌感染的药物的开发。
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3
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4
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Antimicrob Agents Chemother. 2011 Nov;55(11):5277-83. doi: 10.1128/AAC.00582-11. Epub 2011 Aug 8.
5
Clostridium difficile infection: An overview of the disease and its pathogenesis, epidemiology and interventions.
Gut Microbes. 2010 Jul;1(4):234-242. doi: 10.4161/gmic.1.4.12706. Epub 2010 Jun 16.
6
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N Engl J Med. 2011 Feb 3;364(5):422-31. doi: 10.1056/NEJMoa0910812.
7
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Nat Rev Gastroenterol Hepatol. 2011 Jan;8(1):17-26. doi: 10.1038/nrgastro.2010.190. Epub 2010 Nov 30.
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