Metelev Mikhail, Tietz Jonathan I, Melby Joel O, Blair Patricia M, Zhu Lingyang, Livnat Itamar, Severinov Konstantin, Mitchell Douglas A
Institute for Nanobiotechnologies, Saint Petersburg State Polytechnical University, Saint Petersburg 195251, Russia; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Chem Biol. 2015 Feb 19;22(2):241-50. doi: 10.1016/j.chembiol.2014.11.017. Epub 2015 Jan 15.
Natural products are the most historically significant source of compounds for drug development. However, unacceptably high rates of compound rediscovery associated with large-scale screening of common microbial producers have resulted in the abandonment of many natural product drug discovery efforts, despite the increasing prevalence of clinically problematic antibiotic resistance. Screening of underexplored taxa represents one strategy to avoid rediscovery. Herein we report the discovery, isolation, and structural elucidation of streptomonomicin (STM), an antibiotic lasso peptide from Streptomonospora alba, and report the genome for its producing organism. STM-resistant clones of Bacillus anthracis harbor mutations to walR, the gene encoding a response regulator for the only known widely distributed and essential two-component signal transduction system in Firmicutes. To the best of our knowledge, Streptomonospora had been hitherto biosynthetically and genetically uncharacterized, with STM being the first reported compound from the genus. Our results demonstrate that understudied microbes remain fruitful reservoirs for the rapid discovery of novel, bioactive natural products.
天然产物是药物开发中历史意义最为重大的化合物来源。然而，尽管临床上有问题的抗生素耐药性日益普遍，但与常见微生物生产者的大规模筛选相关的化合物重新发现率高得令人无法接受，导致许多天然产物药物发现工作被放弃。对未充分探索的分类群进行筛选是避免重新发现的一种策略。在此，我们报告了链单孢菌素（STM）的发现、分离和结构解析，STM是一种来自白色链单孢菌的抗生素套索肽，并报告了其产生菌的基因组。炭疽芽孢杆菌的STM抗性克隆携带walR基因突变，walR是编码厚壁菌门中唯一已知广泛分布且必需的双组分信号转导系统的应答调节因子的基因。据我们所知，链单孢菌属此前在生物合成和遗传学方面尚未得到表征，STM是该属首次报道的化合物。我们的结果表明，研究不足的微生物仍是快速发现新型生物活性天然产物的丰富来源。
