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

Area of Science:

• Microbiology and Molecular Biology
• Drug Discovery and Medicinal Chemistry

Background:

• Cell-cycle-regulated methyltransferase (CcrM) is vital for bacterial cell division and survival.
• CcrM homologs are found in numerous human pathogens, making it a potential therapeutic target.
• Selective inhibition of bacterial CcrM over human DNA methyltransferases (DNMTs) could lead to novel antibiotics.

Purpose of the Study:

• To screen chemical libraries for novel inhibitors of bacterial CcrM.
• To identify compounds with high selectivity for CcrM compared to human DNMTs.
• To explore new therapeutic strategies against bacterial infections.

Main Methods:

• Screening of two open-access chemical libraries: NCI DCTDDP Diversity Set VII and MMV Global Health Priority Box.
• Identification and structural characterization of CcrM inhibitors.
• Assays to determine the affinity and selectivity of identified inhibitors against CcrM and human DNMT3A.

Main Results:

• Four structurally diverse inhibitors of CcrM were identified from the screened libraries.
• Two of these inhibitors demonstrated micromolar affinity for CcrM.
• These two lead compounds exhibited high selectivity for CcrM over human DNA methyltransferase 3A.

Conclusions:

• The study successfully identified novel, selective inhibitors of bacterial CcrM.
• These compounds represent promising lead candidates for the development of a new class of antibiotics.
• Targeting CcrM offers a viable strategy to combat bacterial pathogens while minimizing off-target effects on human cells.