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

• Type of Material: Article
• Authors: Michelle A. Garrison, Emory University; Andrew R. Mahoney, Emory University; William Wuest, Emory University
• Language: English
• Date: 2020-10-16
• Publisher: Wiley V. C. H. Verlag GMBH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Wiley-VCH GmbH, Weinheim.
• Final Published Version (URL): http://dx.doi.org/10.1002/cmdc.202000604
• Title of Journal or Parent Work: ChemMedChem
• Volume: 16
• Issue: 3
• Start Page: 463
• End Page: 466
• Grant/Funding Information: This work was funded by NIGMS GM119426 and NIH P01 AI083214. Bacterial strains were generously gifted from Dr. Buttaro (Temple University).
• Keywords: Antibacterial; Chemistry, Medicinal; Life Sciences & Biomedicine; MRSA; ammonium compound; Disinfectants; Science & Technology; Infections; Pharmacology & Pharmacy; natural product; antiseptic
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology; Chemistry, General

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.