Nicotinium-based surface-active ionic liquids as antimicrobial surfactants: Micellization properties, antibiofilm activity, and biocompatibility.

Abstract

A new family of nicotinium-based surface-active ionic liquids (CₙNicBr, n = 10-16) was synthesized by N-alkylation of nicotine and characterized by NMR, MS and thermogravimetry (stable to 215 °C). Aqueous association, assessed by conductimetry, fluorescence, tensiometry and dynamic light scattering, gave critical micelle concentrations of 0.58-36 mM and a chain-length-independent apparent monomeric pKa of 5.6 ± 0.1 for the pyrrolidinium nitrogen. CₙNicBr showed generally superior antimicrobial activity against a broad panel of Gram-positive and Gram-negative bacteria and fungi, including MRSA and Candida albicans, versus equivalent-chain cholinium homologues (CₙCholBr), most pronounced at shorter chains, and 2-4-fold greater eradication of preformed MRSA and C. albicans biofilms (MBEC₈₀ 16-128 μg/mL), matching or exceeding benzalkonium chloride and didecyldimethylammonium bromide. Because the pyrrolidinium pKa places the dicationic form below physiological pH, planktonic potency is governed mainly by hydrophobicity, while pH-driven charge enhancement in the acidic biofilm microenvironment (pH 5.5-6.0) may explain the superior eradication. Haemolytic activity (HC₅₀ 17-576 μM) and cytotoxicity against 3T3 and HaCaT cells defined the biocompatibility window: C₁₄NicBr gave the best selectivity against S. aureus/S. epidermidis (HC₅₀/MIC = 25.5), and C₁₂NicBr the widest safety margin (HC₅₀ = 230 μM), the only homologue reaching a rabbit-erythrocyte-based therapeutic index ≥ 10 against MRSA; nucleated-cell-based selectivity indices were substantially narrowed, indicating that the erythrocyte-based indices overestimate the practical safety margin. CₙNicBr thus emerges as a structurally novel antimicrobial surfactant series that, in most comparisons performed here, showed higher antimicrobial and antibiofilm activity than the cholinium benchmark.