Thienoacene-Based Conjugated Oligoelectrolytes for Membrane-Targeting Antimicrobial Approaches: Synergistic Biofilm Eradication and Antimicrobial Resistance Reversal

Membrane-targeting antimicrobials represent a promising class of materials to combat the escalating issue of antimicrobial resistance. Herein, we report a series of membrane-targeting conjugated oligoelectrolytes (COE-<i>n</i>T) featuring thienoacene moieties as π-conjugated cores, designed for tackling antimicrobial resistance. COE-<i>n</i>T exhibited higher activity against Gram-positive bacteria compared to Gram-negative bacteria, with no intrinsic resistance observed in either drug-resistant strain. Notably, a reduction in the π-conjugated length of COE-<i>n</i>T correlated with an increase in membrane permeability and toxicity toward cells and animals. Moreover, COE-<i>n</i>T demonstrated synergistic effects with commercial antibiotics against drug-resistant strains and restored susceptibility to ribosome-targeting antibiotics, such as clindamycin and erythromycin. To illustrate their synergistic potential, the combination of COE-4T and mupirocin was employed to treat <i>methicillin-resistant</i> <i>Staphylococcus aureus</i> infections in a murine wound model, resulting in significant biofilm eradication and enhanced antimicrobial efficacy. This new series of thienoacene-based COEs expands the antimicrobial COEs library with defined structure-activity relationship profiles and demonstrates its potential as a powerful adjunctive therapy for overcoming antimicrobial resistance.