Post Savannah J, Keohane Colleen E, Rossiter Lauren M, Kaplan Anna R, Khowsathit Jittasak, Matuska Katie, Karanicolas John, Wuest William M
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
ACS Infect Dis. 2020 Jun 12;6(6):1372-1377. doi: 10.1021/acsinfecdis.0c00024. Epub 2020 Apr 14.
Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen (). This activity holds promise in the treatment of multidrug resistant infections found in immunocompromised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR investigation enabled identification of succinate dehydrogenase (Sdh) as the biological target in . Herein, we report the target-guided design of new promysalin analogues with varying alkyl chains, one of which is on par with our most potent analogue to date. Computational docking revealed that some analogues have a different orientation in the Sdh binding pocket, placing the terminal carbon proximal to a tryptophan residue. This inspired the design of an extended side chain analogue bearing a terminal phenyl moiety, providing a basis for the design of future analogues.
普罗米萨林是一种小分子天然产物，它能特异性抑制革兰氏阴性病原体（）的生长。这种活性在治疗患有慢性疾病（如囊性纤维化）的免疫功能低下患者中发现的多重耐药感染方面具有前景。2015年，我们实验室完成了首次全合成；随后的类似物设计和构效关系研究使得能够确定琥珀酸脱氢酶（Sdh）为（）中的生物学靶点。在此，我们报告了具有不同烷基链的新型普罗米萨林类似物的靶点导向设计，其中一种与我们迄今为止最有效的类似物相当。计算对接表明，一些类似物在Sdh结合口袋中有不同的取向，使末端碳靠近一个色氨酸残基。这激发了带有末端苯基部分的延长侧链类似物的设计，为未来类似物的设计提供了基础。
