CycP: A Novel Self-Assembled Vesicle-Forming Cyclic Antimicrobial Peptide to Control Drug-Resistant S. aureus

Antimicrobial peptides (AMPs) are considered a promising alternative to conventional antibiotics to fight against the rapid evolution of antibiotic resistance. Other than their potent antimicrobial properties, AMP-based vesicles can be used as efficient drug-delivery vehicles. In the present study, we synthesized and characterized a new cyclic AMP, consisting of all-hydrophobic cores with antimicrobial activity against S. aureus. Interestingly, CycP undergoes supramolecular self-assembly, and self-assembled CycP (sCycP) vesicles are characterized under an electron microscope; however, these vesicles do not display antimicrobial activity. Next, sCycP vesicles are used in combination with SXT (sulfamethoxazole–trimethoprim) vesicles to check the drug loading and delivery capacity of sCycP vesicles to bacterial cell membranes. Interestingly, sCycP vesicles showed synergistic action with SXT vesicles and resulted in a significant reduction in MIC against S. aureus. Further, electron microscopy confirmed the membrane-specific killing mechanism of SXT-loaded sCycP vesicles. Additionally, CycP showed high binding affinities with the β-lactamase of S. aureus, which was one of its possible antimicrobial mechanisms of action. Overall, the results suggested that CycP is a novel self-assembled dual-action cyclic AMP with non-cytotoxic properties that can be used alone as an AMP or a self-assembled drug delivery vehicle for antibiotics to combat S. aureus infections.