Development of Single‐Stranded DNA Bisintercalating Inhibitors of Primase DnaG as Antibiotics

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.

Inhibition of Replication Fork Formation and Progression: Targeting the Replication Initiation and Primosomal Proteins

“…A pyrophosphatase based high-throughput screening was developed and applied for M. tuberculosis, B. anthracis and S. aureus primase activity [39,119,125]. A library consisting of 2556 small molecules (including food and drug administration-approved drugs, molecules that have been used in human therapy, and kinase inhibitors) was screened.…”

“…Of note, the same assay identified dequalinium analogues to inhibit S. aureus primases. However, mechanistic studies showed these inhibitors are ssDNA bisintercalators [125]. M. tuberculosis primase was further screened yielding anthracyclines and aloe-emodin as inhibitors [120,121].…”