Effect of Composition on Antibacterial Activity of Sequence-Defined Cationic Oligothioetheramides

In response to the urgent need for new antibiotic development strategies, antimicrobial peptides and their synthetic mimetics are being investigated as promising alternatives to traditional antibiotics. To facilitate their development into clinically viable candidates, we need to understand what molecular features and physicochemical properties are needed to induce cell death. Within the context of sequence-defined oligothioetheramides (oligoTEAs), we explore the impact of the cationic pendant group and backbone hydrophobicity on the potency and selectivity of antibacterial oligoTEAs. Through antibacterial, cytotoxicity, membrane destabilization, and membrane depolarization assays, we find a strong dependency on the nature of the cationic group and improved selectivity toward bacteria by tuning backbone hydrophobicity. In particular, compounds with the guanidinium headgroup are more potent than those with amines. Finally, we identify a promising oligoTEA, PDT-4G, with enhanced activity in vitro (minimum inhibitory concentration (MIC) ∼ 0.78 μM) and moderate activity in a mouse thigh infection model of methicillin-resistant Staphylococcus aureus. The studies outlined in this work provide insights into the effect of macromolecular physicochemical properties on antibacterial potency. This knowledge base will be vital for researchers engaged in the ongoing development of clinically viable antibacterial agents.