Kimishima Aoi, Hagimoto Daichi, Honsho Masako, Watanabe Yoshihiro, Iwatsuki Masato, Tsutsumi Hayama, Inahashi Yuki, Naher Kamrun, Sakai Kazunari, Kuwae Asaomi, Abe Akio, Asami Yukihiro
Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan; Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan.
Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
Bioorg Med Chem Lett. 2022 Aug 1;69:128779. doi: 10.1016/j.bmcl.2022.128779. Epub 2022 May 8.
Aurodox was originally isolated in 1972 as a linear polyketide compound exhibiting antibacterial activity against Gram-positive bacteria. We have since identified aurodox as a specific inhibitor of the bacterial type III secretion system (T3SS) using our original screening system for inhibition of T3SS-mediated hemolysis in enteropathogenic Escherichia coli (EPEC). In this research, we synthesized 15 derivatives of aurodox and evaluated EPEC T3SS inhibitory activity as well as antibacterial activity against EPEC. One of the derivatives was highly selective for T3SS inhibition, equivalent to that of aurodox, but without exhibiting antibacterial activity (69-fold selectivity). This work revealed the structure-activity relationship for the inhibition of T3SS by aurodox and suggests that the target of T3SS is distinct from the target for antibacterial activity.
奥罗多克斯最初于1972年被分离出来，是一种线性聚酮化合物，对革兰氏阳性菌具有抗菌活性。此后，我们利用我们最初的筛选系统，即抑制肠致病性大肠杆菌（EPEC）中III型分泌系统（T3SS）介导的溶血作用的筛选系统，确定奥罗多克斯是细菌T3SS的特异性抑制剂。在本研究中，我们合成了15种奥罗多克斯的衍生物，并评估了它们对EPEC T3SS的抑制活性以及对EPEC的抗菌活性。其中一种衍生物对T3SS抑制具有高度选择性，与奥罗多克斯相当，但不具有抗菌活性（选择性为69倍）。这项工作揭示了奥罗多克斯抑制T3SS的构效关系，并表明T3SS的靶点与抗菌活性的靶点不同。
