Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis

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• 作者：Ben Gold ; Robert Smith ; Quyen Nguyen ; Julia Roberts ; Yan Ling ; Landys Lopez Quezada ; Selin Somersan ; Thulasi Warrier ; David Little ; Maneesh Pingle ; David Zhang ; Elaine Ballinger ; Matthew Zimmerman ; Véronique Dartois ; Paul Hanson ; Lester A. Mitscher ; Patrick Porubsky ; Steven Rogers ; Frank J. Schoenen ; Carl Nathan ; Jeffrey Aubé
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6027-6044
• 全文大小：1263K
• 年卷期：0
• ISSN：1520-4804

文摘

We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, which only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent upon or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or alternatively an oxadiazole isostere at C-2 of the cephalosporin ring system, a position that is almost exclusively a carboxylic acid in clinically used agents in the class. Representatives of the series kill M. tuberculosis within macrophages without toxicity to the macrophages or other mammalian cells.