title: wrwyrggrywrw is a single-chain functional analog of the Holliday junction-binding homodimer, (wrwycr)2.
abstract: DNA repair pathways in bacteria that use homologous recombination involve the formation and subsequent resolution of Holliday junction (HJ) intermediates. We have previously identified several hexameric peptides that bind to HJs and interfere with HJ processing enzymes in vitro. The peptide WRWYCR and its D-amino acid stereoisomer wrwycr, are potent antibacterial agents. These hexapeptides must form homodimers in order to interact stably with HJs, and inhibit bacterial growth, and this represents a potential limitation. Herein we describe a disulfide bond-independent inhibitor, WRWYRGGRYWRW and its D-stereoisomer wrwyrggrywrw. We have characterized these single-chain, linear analogs of the hexapeptides, and show that in addition to effectively binding to HJs, and inhibiting the activity of DNA repair enzymes that process HJs, they have equal or greater potency against Gram-positive and Gram-negative bacterial growth. The analogs were also shown to cause DNA damage in bacteria, and disrupt the integrity of the bacterial cytoplasmic membrane. Finally, we found that they have little toxicity toward several eukaryotic cell types at concentrations needed to inhibit bacterial growth.
authors.affiliation: Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Rideout
authors.forename: Ilham
authors.initials: I
authors.lastname: Naili
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Boldt
authors.forename: America
authors.initials: A
authors.lastname: Flores-Fujimoto
authors.forename: Sukanya
authors.initials: S
authors.lastname: Patra
authors.forename: Jason E
authors.initials: JE
authors.lastname: Rostron
authors.forename: Anca M
authors.initials: AM
authors.lastname: Segall
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D045566:DNA, Cruciform / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D045566:DNA, Cruciform; D010455:Peptides