Inhibition of the Staphylococcus aureus sortase transpeptidase SrtA by phosphinic peptidomimetics.
During pathogenesis, Gram-positive bacteria utilize surface protein virulence factors such as the MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) to aid the initiation and propagation of infection through adherence to host endothelial tissue and immune system evasion. These virulence-associated proteins generally contain a C-terminal LPXTG motif that becomes covalently anchored to the peptidoglycan biosynthesis intermediate lipid II. In Staphylococcus aureus, deletion of the sortase isoform SrtA results in marked reduction in virulence and infection potential, making it an important antivirulence target. Here we describe the chemical synthesis and kinetic characterization of a nonhydrolyzable phosphinic peptidomimetic inhibitor of SrtA derived from the LPXTG substrate sequence.
Kruger
Ryan G
RG
Department of Biochemistry and Biophysics and the Johnson Research Foundation, The University of Pennsylvania School of Medicine, 905A Stellar-Chance Building, 422 Curie Blvd., Philadelphia, PA 19104-6059, USA.
Barkallah
Salim
S
Frankel
Brenda A
BA
McCafferty
Dewey G
DG
D000595:Amino Acid Sequence; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001426:Bacterial Proteins; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology*
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010748:Phosphopeptides; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases