Quaternary ammonium compounds (QACs) comprise an important class of molecules due to their widespread use as antiseptic agents both commercially and in the household. Unfortunately, the overuse and misuse of QACs has led to the rapid evolution of antibiotic-resistant bacteria, creating the need for the development of potent, yet non-toxic antimicrobials as well as a more thorough understanding of bacterial resistance pathways. Tricepyridinium bromide, a QAC natural product with a unique structure, showed promising inhibitory activity against <i>S. aureus </i>upon its initial isolation, prompting our investigation into its biological activity and mechanism of action. An efficient and reproducible synthetic route was devised to access tricepyridinium bromide as well as four different analogs. The resulting products then underwent biological analysis, and their inhibitory activity was compared to that of two commercially available QACs: cetylpyridinium chloride (CPC) and benzalkonium chloride (BAC). It was found that tricepyridinium and select analogs showed selectivity towards gram-positive bacteria that exceeded that of CPC and BAC while also maintaining low hemolytic activity. In addition, the relationship between tricepyridinium and the QacR transcription factor responsible for regulating a QAC resistance pathway was investigated using molecular modeling. Our studies showed that tricepyridinium and shorter-chain N-alkyl analogs may preferentially bind to this transcription factor, thereby conferring QAC resistance. Our newly synthesized analogs demonstrate the capability to circumvent this transcription factor, providing valuable insight into different mechanisms of antibiotic resistance.

An investigation of the antibacterial activity of tricepyridinium compounds and mechanisms of QAC resistance

ACS Fall 2021

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