1. Development of Single-Stranded DNA Bisintercalating Inhibitors of Primase DnaG as Antibiotics.
- Author
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Green KD, Punetha A, Chandrika NT, Hou C, Garneau-Tsodikova S, and Tsodikov OV
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Cell Line, DNA Primase metabolism, DNA, Single-Stranded chemical synthesis, DNA, Single-Stranded chemistry, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Microbial Sensitivity Tests, Staphylococcus aureus enzymology, Anti-Bacterial Agents pharmacology, DNA Primase antagonists & inhibitors, DNA, Single-Stranded pharmacology, Drug Development, Enzyme Inhibitors pharmacology, Staphylococcus aureus drug effects
- 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 (SaDnaG) 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., (© 2021 Wiley-VCH GmbH.)
- Published
- 2021
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