Dithiocarbamate-Based Sequence-Defined Oligomers as Promising Membrane-Disrupting Antibacterial Agents: Design, Activity, and Mechanism.

Abstract

The emerging prevalence of antimicrobial resistance demands cutting-edge therapeutic agents to treat bacterial infections. We present a synthetic strategy to construct sequence-defined oligomers (SDOs) by using dithiocarbamate (DTC). The antibacterial activity of the synthesized library of SDOs was studied using a Gram-positive B. subtilis and a Gram-negative E. coli. Among SDOs, Dec (with C₁₀ aliphatic chain) was found to be the most promising antibacterial agent exhibiting a minimum inhibitory concentration (MIC) of 3 μg/mL against B. subtilis. Structure-activity relationship studies led to a 400-fold improvement in the MIC within the SDO library. The mode of action of the SDOs was elucidated on a model system, where bacterial membranes mimicking giant unilamellar vesicles (GUVs) were exposed to the SDOs. Membrane disruption and pore formation were found to be the key mechanisms through which SDOs act. In addition, scanning electron microscopy (SEM) and confocal laser scanning microscopy analysis of Dec-treated bacteria confirmed the loss of cell membrane integrity. Finally, the hemolysis assay with SDOs revealed their excellent selectivity toward bacterial cells. Taken together, we developed a modular platform for the synthesis of SDOs having promising antibacterial activity and superior selectivity toward bacteria, with the membrane disruption mode of action confirmed via studies on the model GUV system and SEM analysis.