Garcia Chavez Martin, Garcia Alfredo, Lee Hyang Yeon, Lau Gee W, Parker Erica N, Komnick Kailey E, Hergenrother Paul J
Department of Chemistry, University of Illinois at Urbana-Champaign, Roger Adams Laboratory, 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
ACS Infect Dis. 2021 Feb 12;7(2):493-505. doi: 10.1021/acsinfecdis.0c00869. Epub 2021 Feb 1.
Fusidic acid (FA) is a potent steroidal antibiotic that has been used in Europe for more than 60 years to treat a variety of infections caused by Gram-positive pathogens. Despite its clinical success, FA requires significantly elevated dosing (3 g on the first day, 1.2 g on subsequent days) to minimize resistance, as FA displays a high resistance frequency, and a large shift in minimum inhibitory concentration is observed for resistant bacteria. Despite efforts to improve on these aspects, all previously constructed derivatives of FA have worse antibacterial activity against Gram-positive bacteria than the parent natural product. Here, we report the creation of a novel FA analogue that has equivalent potency against clinical isolates of (s) and () as well as an improved resistance profile when compared to FA. Importantly, this new compound displays efficacy against an FA-resistant strain of in a soft-tissue murine infection model. This work delineates the structural features of FA necessary for potent antibiotic activity and demonstrates that the resistance profile can be improved for this scaffold and target.
夫西地酸（FA）是一种强效甾体抗生素，在欧洲已用于治疗革兰氏阳性病原体引起的各种感染60多年。尽管在临床上取得了成功，但由于FA显示出高耐药频率，并且耐药细菌的最低抑菌浓度有很大变化，为了将耐药性降至最低，FA需要显著提高给药剂量（第一天3克，随后几天1.2克）。尽管努力在这些方面进行改进，但所有先前构建的FA衍生物对革兰氏阳性菌的抗菌活性都比母体天然产物差。在此，我们报告了一种新型FA类似物的创制，该类似物对金黄色葡萄球菌临床分离株的效力与FA相当，并且与FA相比具有改善的耐药性特征。重要的是，这种新化合物在软组织小鼠感染模型中对一株耐FA的金黄色葡萄球菌显示出疗效。这项工作描绘了强效抗生素活性所需的FA结构特征，并证明了针对该支架和靶点可以改善耐药性特征。
