The advent of quaternary ammonium compounds (QACs) as biocides over the past century has had a profound impact on human health. The newly-isolated QAC natural product tricepyridinium bromide shows excellent antimicrobial activity against a range of bacterial pathogens, but its structure seems to preclude a standard membrane perturbation mechanism of action. To investigate further, a concise synthetic route to the natural product and a small library of N-alkyl analogs was designed. Biological analysis highlighted the impressive antibacterial activity of these compounds, which have remarkable selectivity and negligible hemolytic activity as compared to current commercially available antiseptics cetylpiridinium chloride and benzalkonium chloride. Furthermore, computational docking studies on this series of compounds were performed to gain insights into their potential interaction with the QAC resistance-promoting transcription factor QacR. These modeling experiments revealed the potential for future structure-guided design of QAC antimicrobials to circumvent this pathway for the development of resistance.

Development of novel 3,5-diarylpyridinium QACs as potent antibacterial agents

ACS Fall 2021

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