Development of Potent and Selective S. aureus Sortase A Inhibitors Based on Peptide Macrocycles.

Détails

ID Serval
serval:BIB_2F4D38949723
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Development of Potent and Selective S. aureus Sortase A Inhibitors Based on Peptide Macrocycles.
Périodique
ACS Medicinal Chemistry Letters
Auteur(s)
Rentero Rebollo I., McCallin S., Bertoldo D., Entenza J.M., Moreillon P., Heinis C.
ISSN
1948-5875 (Electronic)
ISSN-L
1948-5875
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
7
Numéro
6
Pages
606-611
Langue
anglais
Notes
Publication types: Journal Article Publication Status: epublish
Résumé
Sortases are transpeptidase enzymes that anchor surface proteins, including virulence factors, to the cell wall of Gram-positive bacteria, and they are potential targets for the development of anti-infective agents. While several large compound libraries were searched by high-throughput screening, no high-affinity inhibitors of sortases could be developed to date. Here, we applied phage display to screen billions of peptide macrocycles against sortase A (SrtA) of Staphylococcus aureus (S. aureus). We were able to identify potent and selective inhibitors of SrtA that blocked SrtA-mediated anchoring of synthetic substrates to the surface of live S. aureus cells. A region present in all inhibitory peptides (Leu-Pro-Pro) resembled the natural substrates of SrtA (Leu-Pro-Xaa-Thr-Gly), suggesting that the macrocycles bind to the enzyme's active site and that they form similar molecular contacts as natural substrates. The evolved peptide macrocycles may be used as lead structures for the development of potent peptidomimetic SrtA inhibitors.
Mots-clé
Bicyclic peptide, peptide macrocycle, phage display, sortase, Staphylococcus aureus
Pubmed
Web of science
Création de la notice
08/07/2016 9:46
Dernière modification de la notice
03/03/2018 15:32
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