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.