Antimicrobial Cyclic Peptidomimetics.

Abstract

Antimicrobial resistance is a critical global healthcare issue that urgently needs the development of new antimicrobial agents. Herein, we developed new and discrete cationic amphipathic cyclic peptidomimetics as potential antimicrobial agents to combat multidrug-resistant bacteria. These cyclic oligomers of different alkyl chain lengths are easy to obtain via carbodiimide-mediated condensation reaction and using aza-crown ether as the core reactant. The antimicrobial activity, membrane perturbation effects, and toxicity of the compounds are strongly dependent on the hydrophobic alkyl chain length, as longer lipid chains result in greater antimicrobial potency and membrane disruption but also poorer biocompatibility. For example, cyclic compound bearing 16-carbon chain (CYPEP-C16) has the best bacteriostatic activity against several bacteria strains with minimum inhibitory concentrations of 16 µg mL^-1 but is also toxic, though this can potentially be remedied with different strategies. Critically, the cyclic compounds bearing polyoxazoline-esque backbone can withstand proteolytic degradation and maintain their antimicrobial potency, unlike other polyamide systems. This study thus highlights the potential of these cyclic peptidomimetics as promising new antimicrobial agents.