Antimicrobial activity and cytotoxicity of novel quaternary ammonium and phosphonium salts

Antimicrobial resistance (AMR) poses a global threat to human health, as exemplified by the devastating impact of ESKAPE pathogens, reducing treatment options, increasing disease burden, and elevating death rates due to treatment failure. This looming health threat has rekindled interest in the development of new antimicrobial therapies. In this study, a library of 49 structurally related quaternary heteronium salts (QHSs), such as quaternary ammonium and phosphonium compounds, was screened at a concentration of 32 µg/mL against five ESKAPE pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli), as well as the yeast-like fungus Candida albicans. The preliminary high-throughput screening (HTS) data revealed that QHSs with longer alkyl chain lengths (≥12 carbons) exhibited broad-spectrum antimicrobial activity, with the C14–C16 homologous demonstrating the highest potency. The alkyl-triphenylphosphonium salts 1a–g exhibited the most significant antimicrobial activity among all tested compound series. The compounds identified as active in the initial HTS underwent confirmation assays to determine minimum inhibitory concentration (MIC) and cytotoxicity, following established protocols. Confirmatory assays identified 33 hits (MIC ≤ 16 µg/mL), with 78 % effective at low micromolar concentrations (≤0.25 µg/mL). Seven hits showed safety profiles against HEK-293 cells and red blood cells at concentrations below 32 µg/mL Based on a comparative analysis of their potency against pathogenic microorganisms and cell toxicity, the salts of triphenylphosphonium and quinolinium with linear C8 hydrocarbon substituents (compounds 1b and 5b, respectively), and isoquinolinium, methylpyridinium and triethylammonium with linear C18 hydrocarbon substituents (compounds 3g, 4g, and 7g, respectively) have emerged as the most promising candidates for microbial growth control.