Development of Single‐Stranded DNA Bisintercalating Inhibitors of Primase DnaG as Antibiotics. (31st March 2021)

• Record Type: Journal Article
• Authors: Green, Keith D.; Punetha, Ankita; Chandrika, Nishad Thamban; Hou, Caixia; Garneau‐Tsodikova, Sylvie; Tsodikov, Oleg V.
• Is Part Of: ChemMedChem. Volume 16:Number 12(2021)
• Page Start: 1986
• Page End: 1995
• Publication Date: 2021-03-31
• Subjects: antibacterial agents -- DNA intercalators -- library screening -- medicinal chemistry -- Staphylococcus aureus; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100001
• Languages: English
• ISSNs: 1860-7179

Abstract

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 a bacterium by compromising its membrane. The best compound of this series likely interacts with DnaG directly, inhibits both staphylococcal cell growth and biofilm formation, and displays no significant hemolytic activity or toxicity to mammalian cells. This compound is an excellent lead for further development of a novel anti‐staphylococcal therapeutic. Abstract : The topical antibacterial agent dequalinium is a potent inhibitor of S. aureus primase DnaG even in methicillin‐resistant bacteria. Mechanistic studies of dequalinium analogues show them to be ssDNA bisintercalators that enter the bacterium by compromising its membrane. The best analogue likely interacts with DnaG directly, inhibits bacterial growth and biofilm formation, and has no significant toxicity to mammalian cells.