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

• Published in: ChemMedChem Vol. 16; no. 3; pp. 463 - 466
• Main Authors: Garrison, Michelle A., Mahoney, Andrew R., Wuest, William M.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 04.02.2021; Wiley Subscription Services, Inc
• Subjects: Alkyl compounds; Ammonium; ammonium compound; Ammonium compounds; Analogs; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antimicrobial agents; antiseptic; Benzalkonium chloride; Biological analysis; Cetylpyridinium chloride; Chemistry, Medicinal; Chlorides; Consumer products; Disinfectants; Dose-Response Relationship, Drug; Drug resistance; Escherichia coli - drug effects; Indoles - chemistry; Indoles - pharmacology; Liability; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Models, Molecular; Molecular modelling; Molecular Structure; MRSA; natural product; Natural products; Pharmacology & Pharmacy; Pseudomonas aeruginosa - drug effects; Pyridinium Compounds - chemistry; Pyridinium Compounds - pharmacology; Quaternary ammonium compounds; Quaternary Ammonium Compounds - chemistry; Quaternary Ammonium Compounds - pharmacology; Quaternary ammonium salts; Science & Technology; Selectivity; Staphylococcus - drug effects; Structure-Activity Relationship; antiseptic; ammonium compound; INFECTIONS; DISINFECTANTS; natural product; MRSA; Antibacterial
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202000604

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. Positively irresistible: The use of quaternary ammonium compound (QAC) disinfectants has been the recent subject of controversy regarding their toxicity and development of resistance. Herein we report the synthesis and biological investigation into a class of QACs that show negligible hemolytic activity. Computational modeling studies revealed new insights about QAC resistance and have raised the possibility of rational synthetic design to avoid its development.