Scaffold-Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials

Chembiochem : a European Journal of Chemical Biology
Myles A MitchellKevin P C Minbiole

Abstract

Quaternary ammonium compounds (QACs) are a vital class of antiseptics. Recent investigations into their construction are uncovering novel and potent multicationic variants. Based on a trisQAC precedent, we have implemented a scaffold-hopping approach to develop alternative QAC architectures that display 1-3 long alkyl chains in specific projections from cyclic and branched core structures bearing 3-4 nitrogen atoms. The preparation of 30 QAC structures allowed for correlation of scaffold structure with antimicrobial activity. We identified QACs with limited conformational flexibility that have improved bioactivity against planktonic bacteria as compared to their linear counterparts. We also confirmed that resistance, as evidenced by an increased minimum inhibitory concentration (MIC) for methicillin-resistant Staphylococcus aureus (MRSA) compared to methicillin-susceptible Staphylococcus aureus (MSSA), can reduce efficacy up to 64-fold for monocationic QACs. Differentiation of antimicrobial and anti-biofilm activity, however, was not observed, suggesting that these compounds utilize a non-specific mode of eradication.

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Citations

Dec 30, 2016·ChemMedChem·Saleh E Al-KhalifaKevin P C Minbiole
Apr 11, 2017·Bioorganic & Medicinal Chemistry Letters·Ryan A AllenKevin P C Minbiole
Apr 25, 2017·Chemical Reviews·Akinori OkanoDale L Boger
May 17, 2017·Chembiochem : a European Journal of Chemical Biology·Megan C JenningsWilliam M Wuest
Oct 26, 2018·ChemMedChem·Renee C KontosKevin P C Minbiole
Oct 23, 2018·European Journal of Medicinal Chemistry·Barbara ParrinoStella Cascioferro
Jun 24, 2017·Colloids and Surfaces. B, Biointerfaces·Tara M GallagherKevin L Caran
Jul 3, 2021·International Journal of Molecular Sciences·Anatoly N VereshchaginValentine P Ananikov
Feb 7, 2019·Bioconjugate Chemistry·Fangqin LiuShiyong Zhang

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