title: Cyclic peptide inhibitors of the β-sliding clamp in Staphylococcus aureus.
abstract: Interaction between pairs of Staphylococcus aureus replication proteins was detected in an Escherichia coli based two-hybrid analysis. A reverse two-hybrid system was constructed for selection of compounds that hindered interaction between interacting protein pairs. A number of cyclic peptides, from a library generated by the split intein-mediated circular ligation of peptides and proteins technology, were found to interfere with dimerization of the β-sliding clamp of the replisome. Two 8-mer peptides were analyzed in more detail. Both inhibited DNA replication, led to SOS induction, altered cell morphology and cell death. The peptides were active when added to bacterial cultures indicating that they could traverse the bacterial membrane to find their intracellular target. Peptide specificity was confirmed by overproduction of the putative target (DnaN) which resulted in resistance. The minimum inhibitory concentration was ∼50 μg/ml for S. aureus cells. These compounds may serve as lead candidates for future development into novel classes of antibiotics as well as provide information on the function of the S. aureus replication process.
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kjelstrup
authors.forename: Paula Melo Paulon
authors.initials: PM
authors.lastname: Hansen
authors.forename: Line E
authors.initials: LE
authors.lastname: Thomsen
authors.forename: Paul Robert
authors.initials: PR
authors.lastname: Hansen
authors.forename: Anders
authors.initials: A
authors.lastname: Løbner-Olesen
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D013014:SOS Response, Genetics / Q000187:drug effects / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D010456:Peptides, Cyclic
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