Tricepyridinium-inspired QACs yield potent antimicrobials and provide insight into QAC resistance.
Tricepyridinium-inspired QACs yield potent antimicrobials and provide insight into QAC resistance.
ChemMedChem. 2020 Oct 07;:
Authors: Garrison MA, Mahoney AR, Wuest WM
Abstract
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.
PMID: 33026709 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Garrison MA, Mahoney AR, Wuest WM Tags: ChemMedChem Source Type: research
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