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Development of Single‐Stranded DNA Bisintercalating Inhibitors of Primase DnaG as Antibiotics
Author(s) -
Green Keith D.,
Punetha Ankita,
Chandrika Nishad Thamban,
Hou Caixia,
GarneauTsodikova Sylvie,
Tsodikov Oleg V.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100001
Subject(s) - dnag , primase , bacteria , staphylococcus aureus , chemistry , microbiology and biotechnology , bacterial cell structure , dna , antibiotics , antibacterial activity , antibacterial agent , biochemistry , biology , dna replication , reverse transcriptase , rna , genetics , circular bacterial chromosome , gene
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.