Rodriguez Rodrigo A, Barrios Steed Danielle, Kawamata Yu, Su Shun, Smith Peter A, Steed Tyler C, Romesberg Floyd E, Baran Phil S
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
J Am Chem Soc. 2014 Oct 29;136(43):15403-13. doi: 10.1021/ja508632y. Epub 2014 Oct 20.
Antibiotic-resistant bacteria present an ongoing challenge to both chemists and biologists as they seek novel compounds and modes of action to out-maneuver continually evolving resistance pathways, especially against Gram-negative strains. The dimeric pyrrole-imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture. This full account traces the strategy used to develop a second-generation route to key spirocycle 9, culminating in a practical synthesis of the axinellamines and enabling their discovery as broad-spectrum antibacterial agents, with promising activity against both Gram-positive and Gram-negative bacteria. While their detailed mode of antibacterial action remains unclear, the axinellamines appear to cause secondary membrane destabilization and impart an aberrant cellular morphology consistent with the inhibition of normal septum formation. This study serves as a rare example of a natural product initially reported to be devoid of biological activity surfacing as an active antibacterial agent with an intriguing mode of action.
抗生素耐药细菌对化学家和生物学家来说一直是一项挑战，因为他们要寻找新的化合物和作用方式来战胜不断演变的耐药途径，尤其是针对革兰氏阴性菌的耐药途径。二聚吡咯 - 咪唑生物碱代表了一类独特的海洋天然产物，具有多样的主要生物活性和化学结构。本完整报告追溯了用于开发关键螺环9的第二代路线的策略，最终实现了阿新环胺类化合物的实用合成，并使其被发现为广谱抗菌剂，对革兰氏阳性菌和革兰氏阴性菌均具有有前景的活性。虽然它们详细的抗菌作用模式尚不清楚，但阿新环胺类化合物似乎会导致二次膜不稳定，并呈现出与正常隔膜形成受抑制一致的异常细胞形态。这项研究是一个罕见的例子，一种最初报道无生物活性的天然产物后来成为具有有趣作用方式的活性抗菌剂。
