Tricepyridinium-inspired QACs yield potent antimicrobials and provide insight into QAC resistance.

Michelle A Garrison, Andrew R Mahoney, William M Wuest

ChemMedChem 2021 Feb 04

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Quaternary ammonium compounds (QACs) comprise a large class of surfactants, consumer products, and disinfectants. The recently-isolated QAC natural product tricepyridinium bromide displays potent inhibitory activity against S. aureus but due to its unique structure, its mechanism of action remains unclear. A concise synthetic route to access tricepyridinium analogs was thus designed and four N-alkyl compounds were generated in addition to the natural product. Biological analysis of these compounds revealed that they display remarkable selectivity towards clinically-relevant Gram-positive bacteria exceeding that of commercially-available QACs such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BAC) while having little to no hemolytic activity. Molecular modeling studies revealed that tricepyridinium and shorter-chain N-alkyl analogs may preferentially bind to the QacR transcription factor leading to potential activation of the QAC resistance pathway found in MRSA; however, our newly synthesized analogs are able to overcome this liability. © 2020 Wiley-VCH GmbH.

Citation

Michelle A Garrison, Andrew R Mahoney, William M Wuest. Tricepyridinium-inspired QACs yield potent antimicrobials and provide insight into QAC resistance. ChemMedChem. 2021 Feb 04;16(3):463-466