Emmanuel T. Adeniyi, Marco Kruppa, Stefania De Benedetti, Kevin C. Ludwig, Violetta Krisilia, Tobias R. Wassenberg, Melissa Both, Tanja Schneider, Thomas J. J. Müller* and Rainer Kalscheuer*,
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引用次数: 0
摘要
尽管在疫苗开发和临床试验方面做出了巨大努力,并有几种临床前有效的候选药物参与其中,但每年仍有约 10 万人死于耐甲氧西林金黄色葡萄球菌(MRSA)感染。因此,有必要开发针对这种耐药细菌病原体的替代疗法。此前,我们利用 Masuda borylation-Suzuki 偶联(MBSC)序列合成并修饰了天然存在的双吲哚生物碱、阿洛卡辛 A、hyrtinadine A 和 scalaradine A,得到的衍生物在体外和体内均显示出强大的抗菌功效。在此,我们报告了一种改进的单锅 MBSC 方案,该方案用于合成以前报道过的和几种未曾描述过的 N-对甲基苯磺酰保护双吲哚,这些双吲哚具有抗 MRSA 活性,对人类单核细胞和肾细胞系具有适度的细胞毒性。机理研究表明,双吲哚通过与脂质 II 和膜磷脂的杂乱相互作用影响革兰氏阳性细菌的细胞质膜,同时迅速消散膜电位。具有杀菌作用且与脂质 II 相互作用的先导化合物 5c 和 5f 可能是开发抗 MRSA 药物的有趣起点。
Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus
About 100,000 deaths are attributed annually to infections with methicillin-resistant Staphylococcus aureus (MRSA) despite concerted efforts toward vaccine development and clinical trials involving several preclinically efficacious drug candidates. This necessitates the development of alternative therapeutic options against this drug-resistant bacterial pathogen. Using the Masuda borylation-Suzuki coupling (MBSC) sequence, we previously synthesized and modified naturally occurring bisindole alkaloids, alocasin A, hyrtinadine A and scalaradine A, resulting in derivatives showing potent in vitro and in vivo antibacterial efficacy. Here, we report on a modified one-pot MBSC protocol for the synthesis of previously reported and several undescribed N-tosyl-protected bisindoles with anti-MRSA activities and moderate cytotoxicity against human monocytic and kidney cell lines. In continuation of the mode of action investigation of the previously synthesized membrane-permeabilizing hit compounds, mechanistic studies reveal that bisindoles impact the cytoplasmic membrane of Gram-positive bacteria by promiscuously interacting with lipid II and membrane phospholipids while rapidly dissipating membrane potential. The bactericidal and lipid II-interacting lead compounds 5c and 5f might be interesting starting points for drug development in the fight against MRSA.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.