新型抗结核药物研发：微生物非常规培养与沉默基因激活策略

Development of new anti-tuberculosis drugs: the strategy of unconventional microbial culture and silencing gene activation

摘要:

由结核分枝杆菌感染引起的结核病是人类重要传染病之一。临床上结核菌耐药性日趋严重，不断出现的耐多药及广泛耐药结核病患者，使现有的一线至五线药物不能满足结核病防控需求。微生物来源的天然产物是药物先导化合物的重要来源。环境中存在大量常规培养条件下未培养微生物，同时微生物基因组中也存在大量未被表达的“沉默代谢途径”。运用各种方法对未培养微生物进行再培养，同时激活微生物的沉默代谢途径，进而获得潜在的新型抗生素药物已成为目前研究热点。文中系统阐述了近年来获取天然化合物所采用的微生物非常规培养技术及沉默代谢途径激活策略，同时总结了利用这两种方法获得的新型抗结核天然产物，并展望了这些方法在抗结核药物进一步研发中的应用前景。

关键词:结核分枝杆菌，未培养微生物，沉默基因，单株菌-多次级代谢产物 (OSMAC)

Abstract:

Tuberculosis (TB), caused by Mycobacterium tuberculosis, has become a major human infectious disease. The existing first-line and second-line TB drugs have poor treatment outcomes in patients with MDR-TB and XDR-TB. There is an urgent need for new and better drugs to treat tuberculosis due to lengthy and complex treatment regimens and a rising problem of drug resistance. Microbial-derived natural products have revealed enormous reservoirs of as yet untapped lead compounds. In this review, we discuss the strategies that have been developed in bacteria and fungi to isolation of non-culturable microorganisms and activation of silent biosynthetic gene clusters involved in the study of microbial-derived natural products. This review also highlights recent advances in microbial-derived natural products with anti-tuberculosis activity using these methods.

Key words:Mycobacterium tuberculosis, un-cultured microorganisms, silent genes, one strain-many compounds (OSMAC)