Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
Institute of Organic Chemistry and Biomolecular Drug Research Centre (BMWZ), Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover, Germany.
J Med Chem. 2024 Oct 10;67(19):17162-17190. doi: 10.1021/acs.jmedchem.4c00927. Epub 2024 Sep 20.
Cystobactamids have a unique oligoarylamide structure and exhibit broad-spectrum activity against Gram-negative and Gram-positive bacteria. In this study, the central α-amino acid of the cystobactamid scaffold was modified to address the relevance of stereochemistry, hydrogen bonding and polarity by 33 derivatives. As demonstrated by three matched molecular pairs, l-amino acids were preferred over d-amino acids. A rigidification to a six-membered system stabilized the bioactive conformation for the on-target gyrase, but did not improve antimicrobial activity. Compound CN-CC-861, carrying a propargyl side chain, had more than 16-fold lower minimal inhibitory concentration (MIC) values against , and strains, compared to known analogues. Moreover, CN-CC-861 retained activity against multidrug-resistant enterococci, displayed strong bactericidal activity, moderate-low frequencies of resistance and efficacy in a neutropenic thigh infection model with . Overall, the findings will guide the design of new promising structures with higher activities and broader spectrum.
胱抑菌素具有独特的寡肽酰胺结构，对革兰氏阴性和革兰氏阳性细菌表现出广谱活性。在这项研究中，通过 33 种衍生物对胱抑菌素支架的中心 α-氨基酸进行了修饰，以解决立体化学、氢键和极性的相关性。如三个匹配的分子对所示，l-氨基酸优先于 d-氨基酸。刚性化为六元系统稳定了针对靶标拓扑异构酶的生物活性构象，但没有提高抗菌活性。带有炔丙基侧链的化合物 CN-CC-861 对 、 和 菌株的最小抑菌浓度（MIC）值比已知类似物低 16 倍以上。此外，CN-CC-861 对耐多药肠球菌仍具有活性，显示出较强的杀菌活性、适度低的耐药频率以及在中性粒细胞减少性大腿感染模型中的疗效。总的来说，这些发现将指导设计具有更高活性和更广泛谱的新型有前途的结构。
