Identification of a small molecule with activity against drug-resistant and persistent tuberculosis.
نویسندگان
چکیده
A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.
منابع مشابه
تشخیص موتاسیون در کدون 315 ژن katG، مارکر مقاومت به ایزونیازید در سوشهای مایکوباکتریوم توبرکولوزیس جدا شده از بیماران اصفهان و تهران با روش PCR-RFLP
Background and Objective: Drug resistance to tuberculosis is continuously increasing and is a significant threat to tuberculosis control programs because afew effective drugs are present against Mycobacterium tuberculosis. Although isoniazid (INH) is the most effective drug against tuberculosis, resistance to this drug also develops readily. Mutations in katG, specially the Ser315Thr substituti...
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عنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 110 27 شماره
صفحات -
تاریخ انتشار 2013