Department of Biochemistry and Biomedical Sciences, MG DeGroote Institute for Infectious Disease Research, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
J Antibiot (Tokyo). 2010 Apr;63(4):177-82. doi: 10.1038/ja.2010.13. Epub 2010 Mar 12.
The bacterial genus Streptomyces is endowed with a remarkable secondary metabolism that generates an enormous number of bioactive small molecules. Many of these genetically encoded small molecules are used as antibiotics, anticancer agents and as other clinically relevant therapeutics. The rise of resistant pathogens has led to calls for renewed efforts to identify antimicrobial activities, including expanded screening of streptomycetes. Indeed, it is known that most strains encode >20 secondary metabolites and that many, perhaps most of these, have not been considered for their possible therapeutic use. One roadblock is that many strains do not express their secondary metabolic gene clusters efficiently under laboratory conditions. As one approach to this problem, we have used alleles of a pleiotropic regulator of secondary metabolism from Streptomyces coelicolor to activate secondary biosynthetic gene clusters in heterologous streptomycetes. In one case, we demonstrate the activation of pulvomycin production in S. flavopersicus, a metabolite not previously attributed to this species. We find that the absA1-engineered strains produced sufficient material for purification and characterization. As a result, we identified new, broad-spectrum antimicrobial activities for pulvomycin, including a potent antimicrobial activity against highly antibiotic-resistant Gram-negative and Gram-positive pathogens.
放线菌属的细菌具有显著的次生代谢能力，能够产生大量的生物活性小分子。其中许多遗传编码的小分子被用作抗生素、抗癌剂和其他临床相关的治疗药物。耐药病原体的出现促使人们再次呼吁识别抗菌活性，包括扩大对链霉菌的筛选。事实上，已知大多数菌株编码 >20 种次生代谢物，而且许多（也许是大多数）这些代谢物尚未被考虑用于其可能的治疗用途。一个障碍是，许多菌株在实验室条件下不能有效地表达其次生代谢基因簇。作为解决这个问题的一种方法，我们使用了来自变铅青链霉菌的一种次生代谢多效调节因子的等位基因，来激活异源链霉菌中的次生生物合成基因簇。在一种情况下，我们证明了 pulvomycin 在黄色链霉菌中的产生被激活，而这种代谢物以前并未归因于该种。我们发现，经过 absA1 工程改造的菌株产生了足够的物质用于纯化和表征。结果，我们确定了 pulvomycin 的新的、广谱的抗菌活性，包括对高度耐药的革兰氏阴性和革兰氏阳性病原体的强大抗菌活性。
