Development of single-stranded DNA bisintercalating inhibitors of primase DnaG as antibiotics

ChemMedChem. 2021 Mar 12. doi: 10.1002/cmdc.202100001. Online ahead of print.

ABSTRACT

Many essential enzymes in bacteria remain promising potential targets of antibacterial agents. In this study, we discovered that dequalinium, a topical antibacterial agent, is an inhibitor of Staphylococcus aureus primase DnaG ( Sa DnaG) with low micromolar minimum inhibitory concentrations against several S. aureus strains, including methicillin-resistant bacteria. Mechanistic studies of dequalinium and a series of nine of its synthesized analogues revealed that these compounds are single-stranded DNA bisintercalators that penetrate the bacterium by compromising its membrane. The best compound of this series (compound 2 ) likely interacts with DnaG directly, inhibits both staphylococcal cell growth and biofilm formation, and displays no significant hemolytic activity or toxicity to mammalian cells. Compound 2 is an excellent lead for further development of a novel anti-staphylococcal therapeutic.

PMID:33711198 | DOI:10.1002/cmdc.202100001