Tan Yun Xuan, Peters David S, Walsh Shawn I, Holcomb Matthew, Santos-Martins Diogo, Forli Stefano, Romesberg Floyd E
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
J Nat Prod. 2020 Jul 24;83(7):2112-2121. doi: 10.1021/acs.jnatprod.9b01174. Epub 2020 Jul 2.
The arylomycins are a class of natural product antibiotics that inhibit bacterial type I signal peptidase and are under development as therapeutics. Four classes of arylomycins are known, arylomycins A-D. Previously, we reported the synthesis and analysis of representatives of the A, B, and C classes and showed that their spectrum of activity has the potential to be much broader than originally assumed. Along with a comparison of the mechanism of acquired and innate resistance, this led us to suggest that the arylomycins are latent antibiotics, antibiotics that once possessed broad-spectrum activity, but which upon examination today, have only narrow spectrum activity due to prior selection for resistance in the course of the competition with other microorganisms that drove their evolution in the first place. Interestingly, actinocarbasin, the only identified member of the arylomycin D class, has been reported to have activity against MRSA. To confirm and understand this activity, several actinocarbasin derivatives were synthesized. We demonstrate that the previously reported structure of actinocarbasin is incorrect, identify what is likely the correct scaffold, confirm that scaffold has activity against MRSA, and determine the origin of this activity.
芳基霉素是一类天然产物抗生素，可抑制细菌I型信号肽酶，目前正作为治疗药物进行研发。已知有四类芳基霉素，即芳基霉素A - D。此前，我们报道了A、B和C类芳基霉素代表物的合成与分析，并表明它们的活性谱可能比最初设想的要广泛得多。通过比较获得性耐药和固有耐药的机制，这使我们提出芳基霉素是潜在抗生素，即曾经具有广谱活性，但如今经检测，由于在与最初推动其进化的其他微生物竞争过程中预先选择了耐药性，所以仅具有窄谱活性。有趣的是，据报道，芳基霉素D类中唯一已鉴定的成员放线碳霉素对耐甲氧西林金黄色葡萄球菌（MRSA）具有活性。为了证实并了解这种活性，合成了几种放线碳霉素衍生物。我们证明了先前报道的放线碳霉素结构是错误的，确定了可能正确的骨架，证实该骨架对MRSA具有活性，并确定了这种活性的来源。
