Organic Chemistry, Saarland University, Campus Building C4.2, 66123 Saarbruecken, Germany.
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
Mar Drugs. 2022 Oct 3;20(10):632. doi: 10.3390/md20100632.
Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of . The cyclic peptides target the AAA+ protein ClpC1 that, together with the peptidases ClpP1/ClpP2, forms an essential ATP-driven protease. Derivatives of the ilamycins with a simplified tryptophane unit are synthesized in a straightforward manner. The ilamycin derivative with a cyclic hemiaminal structure is active in the nM-range against several mycobacterial strains and shows no significant cytotoxicity. In contrast, derivative , with a glutamic acid at this position, is significantly less active, with MICs in the mid µM-range. Detailed investigations of the mode of action of indicate that deregulates ClpC1 activity and strongly enhances ClpC1-WT ATPase activity. The consequences of on ClpC1 proteolytic activities were substrate-specific, suggesting dual effects of on ClpC1-WT function. The positive effect relates to ClpC1-WT ATPase activation, and the negative to competition with substrates for binding to the ClpC1 NTD.
伊拉菌素/鲁福霉素是含有特殊氨基酸的海洋环七肽。这些化合物由 产生，对多种分枝杆菌具有很强的活性，包括耐多药的 。环状肽靶向 AAA+蛋白 ClpC1，它与肽酶 ClpP1/ClpP2 一起形成一种必需的 ATP 驱动蛋白酶。伊拉霉素的简化色氨酸单元的衍生物以简单的方式合成。具有环状亚氨基结构的伊拉霉素衍生物 在纳摩尔范围内对几种分枝杆菌菌株有效，且没有明显的细胞毒性。相比之下，该位置带有谷氨酸的衍生物 则活性显著降低，MIC 值在中微摩尔范围内。对 的作用模式的详细研究表明， 使 ClpC1 失活，并强烈增强 ClpC1-WT ATP 酶活性。 对 ClpC1 蛋白水解活性的影响具有底物特异性，表明 对 ClpC1-WT 功能具有双重影响。积极的影响与 ClpC1-WT ATP 酶的激活有关，而消极的影响则与与 ClpC1 NTD 结合的底物竞争有关。
