Synthetically accessible naphthalene-based rigid-core electrolytes as membrane-active antibacterial agents against drug-resistant pathogens.

Abstract

The growing threat of antimicrobial resistance (AMR) underscores the need for antibacterial scaffolds that act through mechanisms distinct from those of conventional antibiotics. Conjugated oligoelectrolytes (COEs) are membrane-active antimicrobials, although stilbene-containing representatives can present scaffold-specific challenges associated with alkene stability and synthetic accessibility. Here, we report a naphthalene-based rigid-core electrolyte (RCE) platform that removes the phenylene-vinylene linker while retaining potent antibacterial activity. The RCEs were accessed through a two-step, transition-metal-free route, and the lead compound N6P displayed activity against the tested ESKAPE representatives (MICs = 1-8 μg/mL), Mycobacterium abscessus (MIC = 4 μg/mL), and Streptococcus pneumoniae (MIC = 1 μg/mL). DiSC3(5) depolarization, ANS uptake, TEM imaging and DAPI/PI imaging were consistent with bacterial membrane perturbation. N6P was rapidly bactericidal against MRSA, retained activity in serum-supplemented medium, produced only a fourfold maximum MIC increase during 14 passages, and reduced viable bacteria in established MRSA biofilms. In a murine MRSA wound model, N6P and N6-Br reduced bacterial burden by 3.2-4.8 log10 CFU at doses of 0.05-0.25 mg/kg. Serum biochemical profiling at 0.25 mg/kg showed no consistent treatment-related changes, while histological examination at doses up to 0.75 mg/kg revealed no overt abnormalities under the conditions evaluated. These findings identify compact scaffold rigidity, linker length, and cation identity as important design variables for this RCE series and support further pharmacokinetic, formulation, and tolerability studies.