Thapa Sudarshan Singh, Grove Anne
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.
Antibiotics (Basel). 2019 Sep 23;8(4):160. doi: 10.3390/antibiotics8040160.
The emergence of multiple antibiotic resistant bacteria has pushed the available pool of antibiotics to the brink. Bacterial secondary metabolites have long been a valuable resource in the development of antibiotics, and the genus has recently emerged as a source of novel compounds with antibacterial, antifungal, and anti-cancer activities. Genome mining has contributed to the identification of biosynthetic gene clusters, which encode enzymes that are responsible for synthesis of such secondary metabolites. Unfortunately, these large gene clusters generally remain silent or cryptic under normal laboratory settings, which creates a hurdle in identification and isolation of these compounds. Various strategies, such as changes in growth conditions and antibiotic stress, have been applied to elicit the expression of these cryptic gene clusters. Although a number of compounds have been isolated from different species, the mechanisms by which the corresponding gene clusters are regulated remain poorly understood. This review summarizes the activity of well characterized secondary metabolites from species and the role of local regulators in their synthesis, and it highlights recent evidence for the role of global regulators in controlling production of secondary metabolites. We suggest that targeting global regulators holds great promise for the awakening of cryptic gene clusters and for developing better strategies for discovery of novel antibiotics.
多重耐药细菌的出现已将可用的抗生素库推向了边缘。细菌次级代谢产物长期以来一直是抗生素开发中的宝贵资源，最近该属已成为具有抗菌、抗真菌和抗癌活性的新型化合物的来源。基因组挖掘有助于识别生物合成基因簇，这些基因簇编码负责合成此类次级代谢产物的酶。不幸的是，这些大的基因簇在正常实验室条件下通常保持沉默或隐蔽，这给这些化合物的鉴定和分离带来了障碍。已应用各种策略，如改变生长条件和抗生素应激，来诱导这些隐蔽基因簇的表达。尽管已从不同的物种中分离出许多化合物，但相应基因簇的调控机制仍知之甚少。本综述总结了来自物种的特征明确的次级代谢产物的活性及其局部调节因子在其合成中的作用，并强调了全球调节因子在控制次级代谢产物产生中的作用的最新证据。我们认为，针对全球调节因子对于唤醒隐蔽基因簇和开发发现新型抗生素的更好策略具有巨大潜力。
