| The overuse of antibiotics has imposed immense selective pressure on Staphylococcal bacteria which has resulted in the increased evolution of antibiotic-resistant bacteria such as Methicillin-resistant S. aureus to the point where last-line agents are now obsolete. Therefore, there is great pressure to develop novel approaches to combat bacterial infections while minimising the development of resistance. Here, the development of compounds which inhibit bacterial quorum sensing through antagonism of the accessory gene regulator (agr) display promise as a new generation of therapeutics. In this study, which focused on S. aureus group I, the previously reported agr inhibitor tr-Ac(Ala5)-AIP-1 was subjected to structure-activity-relationship studies with peptides synthesised under continuous-flow solid-phase conditions. Evaluation of the agrC-I inhibitory activities of the resulting library of cyclic peptides demonstrated that the three analogues, compound 16, 18 and 13 displayed sub-nanomolar inhibitory activities (IC50 < 0.7 nM, IC50 < 0.7 nM & IC50 < 0.7 nM, respectively). It is hopeful that the principle pharmacophores for agrC-I developed in this study will provide a valuable platform for the development of global agr-inhibitors as next-generation anti-bacterial therapeutics. |
