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 <b>cF</b> as the lead compound, with activity against Gram-positive and Gram-negative bacteria, low cytotoxicity (HepG2 IC₅₀ ∼ 614 μg/mL), and the highest <i>in vivo</i> systemic tolerance. <i>Staphylococcus aureus</i> and <i>Klebsiella pneumoniae</i> showed a low tendency to develop <b>cF</b> resistance after acute or prolonged exposures. We find that <b>cF</b> was efficacious against <i>K. pneumoniae</i> clinical isolates regardless of the drug resistance profile. Additionally, <b>cF</b> was bactericidal, inhibited biofilm formation, killed established biofilms, and suppressed the pro-inflammatory cytokine response to lipopolysaccharide (LPS). Systemically delivered <b>cF</b> 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.