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DNA repair is the target of novel antibiotics

  • Author(s): Gunderson, Carl Wayne
  • et al.
Abstract

DNA repair is an important cellular process that is conserved in Bacteria, Archaea, and Eukaryotes. The process of DNA repair involves many different proteins that function to create and process branched DNA intermediates. The branched intermediates include 3-way branches (such as replication forks) and 4-way branches (Holliday junctions). Previously, our laboratory isolated peptides based on their ability to inhibit site-specific recombination. The biochemical activity of the most potent peptides was found to be a result of their specific binding to Holliday junctions and branched DNA intermediates. We hypothesized that if the peptides bind to these 3- and 4-armed intermediates and inhibit their resolution, we would expect them to have antimicrobial activity. We have found that some of these hexapeptides are potent antimicrobials, bactericidal against both Gram+ and Gram- Bacteria. The hexapeptides cause DNA segregation abnormalities, filamentation, and DNA damage. Using epifluorescence microscopy and flow cytometry, we have extensively characterized the physiology of bacterial cells treated with these peptides. Our model proposes that the peptides kill bacterial cells by trapping the intermediates in the repair of endogenous or exogenous DNA damage and preventing its completion. We show that, in agreement with our predictions, our most potent peptide inhibitor causes double strand breaks and DNA fragmentation in Salmonella enterica Typhimurium as shown by pulsed field gel electrophoresis (PFGE). We have compared the extent of peptide-dependent DNA fragmentation in wild-type cells and in mutants with defects in DNA repair. The data indicate that peptide treatment creates substrates for processing by the RecBCD double strand break (DSB) repair pathway and the RecFOR single strand break (SSB) repair pathway. We propose that the peptides influence the processing of DNA repair intermediates by increasing the time that it takes cellular machinery to process of Holliday junctions and branched intermediates. The data support our previous hypothesis that peptide d- wrwycr inhibits bacterial growth by exacerbating DNA damage and interfering with DNA repair

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