Effects of Halogen Substitution on the Antibiotic Characteristics of Conjugated Oligoelectrolytes.

Conjugated oligoelectrolytes (COEs) are amphiphiles that can exhibit antimicrobial activity. With the view to further develop structure-activity relationships, we report here a series of amidinium COEs with halogen-substituted distyrylbenzene cores and an exploration of the impacts of substitution regiochemistries. We identified cF as the lead compound, with activity against Gram-positive and Gram-negative bacteria, low cytotoxicity (HepG2 IC50 ∼ 614 μg/mL), and the highest in vivo systemic tolerance. Staphylococcus aureus and Klebsiella pneumoniae showed a low tendency to develop cF resistance after acute or prolonged exposures. We find that cF was efficacious against K. pneumoniae clinical isolates regardless of the drug resistance profile. Additionally, cF was bactericidal, inhibited biofilm formation, killed established biofilms, and suppressed the pro-inflammatory cytokine response to lipopolysaccharide (LPS). Systemically delivered cF achieved ≥1-log reduction in bacterial load in an acute murine lung infection model and displayed an extended residence time in lungs, which could allow for a unique single-dosing strategy.