Allosteric Inhibitors of Cell-Cycle-Regulated Methyltransferase for Novel Antibiotic Development

Abstract

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.