Hernandez Ivan, Jin Kyongyun Claire, Yang Yicheng, Konttinen Olivia, Lantz Alexandra, Zhao Yifan, Squire Ian, Pettus Thomas R R, Reich Norbert O
The Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States.
Biomolecular Science and Engineering, University of California, Santa Barbara, California 93106-9510, United States.
ACS Omega. 2025 Apr 9;10(15):15775-15780. doi: 10.1021/acsomega.5c01540. eCollection 2025 Apr 22.
Cell-cycle-regulated methyltransferase (CcrM) plays a crucial role in regulating important cellular processes that are essential for proper cell division and growth; disruptions of these processes can attenuate the bacteria's viability. Notably, CcrM homologs are present across a set of diverse human pathogens, suggesting that selective inhibition of CcrM over human DNA methyltransferases (DNMT's) could offer a new strategy for combating human bacterial pathogens, leading to the development of novel antibiotics. Herein, we report the screening of two open-access chemical libraries-the National Cancer Institute Developmental Therapeutic Program Diversity Set VII and Medicines for Malaria Venture Global Health Priority Box-and identified four structurally diverse inhibitors of CcrM. Among these, two inhibitors displayed both micromolar affinity and high selectivity for CcrM over human DNA methyltransferase 3A, highlighting their potential as leads for a new class of antibiotics.
细胞周期调控甲基转移酶（CcrM）在调节对细胞正常分裂和生长至关重要的重要细胞过程中起着关键作用；这些过程的破坏会削弱细菌的活力。值得注意的是，CcrM 同源物存在于一系列不同的人类病原体中，这表明对 CcrM 的选择性抑制相对于人类 DNA 甲基转移酶（DNMT）而言，可能为对抗人类细菌病原体提供一种新策略，从而推动新型抗生素的开发。在此，我们报告了对两个开放获取化学文库——美国国立癌症研究所（National Cancer Institute）的发展治疗计划多样性集 VII（Developmental Therapeutic Program Diversity Set VII）和疟疾药物事业组织（Medicines for Malaria Venture）的全球健康优先药物库（Global Health Priority Box）——的筛选，并鉴定出了四种结构不同的 CcrM 抑制剂。其中，两种抑制剂对 CcrM 表现出微摩尔亲和力且相对于人类 DNA 甲基转移酶 3A 具有高选择性，突出了它们作为新型抗生素先导物的潜力。
