Cyclic peptide inhibitors of staphylococcal virulence prepared by Fmoc-based thiolactone peptide synthesis.
Virulence factor production in Staphylococcus aureus is largely under the control of the accessory gene regulator (agr) quorum sensing system. There are four agr groups, all of which exhibit bacterial interference: each agr type synthesizes a cyclic autoinducing peptide (AIP) with a distinct sequence that activates its cognate AgrC receptor and inhibits activation of others. To better understand inhibitory AIP-AgrC interactions, we aimed to identify the minimal molecular determinants required to inhibit both non-cognate and cognate receptors. This minimization of the AIP pharmacophore also may have therapeutic relevance as the use of native AIPs to block virulence of non-cognate agr strains can prevent the establishment of an infection in vivo. We synthesized and evaluated the inhibitory activities of 10 AIP derivatives based on a truncated AIP analogue that inhibits all four agr types. To carry out the rapid, parallel synthesis of these peptides, we employed a new linker for Fmoc-based thioester peptide synthesis. Our results identify key structural elements that are necessary for AgrC inhibition and reveal key differences between non-cognate and cognate inhibitory requirements.
George
Elizabeth A
EA
The Laboratory of Synthetic Protein Chemistry, Rockefeller University, New York, New York 10065, USA.
Novick
Richard P
RP
Muir
Tom W
TW
D000596:Amino Acids / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D005449:Fluorenes / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001618:beta-Lactamases / Q000378:metabolism
C095698:Agr protein, Staphylococcus aureus; D000596:Amino Acids; D001426:Bacterial Proteins; D005449:Fluorenes; D007783:Lactones; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010456:Peptides, Cyclic; D013438:Sulfhydryl Compounds; D015534:Trans-Activators; D037521:Virulence Factors; D001618:beta-Lactamases