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Alkhalifa S , Jennings M , Granata D , Klein M , Wuest WM , Minbiole K , Carnevale V
Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study
Chembiochem. 2019 Dec 20
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The mechanism of action of quaternary ammonium compound (QAC) antiseptics has long been assumed to be straightforward membrane disruption, although the process of approaching and entering the membrane has little modelling precedent. Furthermore, questions have more recently arisen regarding bacterial resistance mechanisms, and why select classes of QACs (specifically, multicationic QACs) are less prone to resistance. In order to better understand such subtleties, a series of molecular dynamics simulations were utilized to help identify these molecular determinants, directly comparing mono-, bis-, and triscationic QACs in simulated membrane intercalation models. Three distinct membranes were simulated, mimicking the surfaces of E. coli and S. aureus, as well as a neutral phospholipid control. By analyzing the resulting trajectories in the form of a timeseries analysis, insight was gleaned regarding the significant steps and interactions involved in the destabilization of phospholipid bilayers within the bacterial membranes. Finally, to more specifically probe the effect of the hydrophobic section of the amphiphile that presumably penetrates the membrane, a series of alkyl- and ester-based biscationic quaternary ammonium compounds were prepared, tested for antimicrobial activity against both Gram-positive and Gram-negative bacteria, and modelled.
1439-7633 Alkhalifa, Saleh Jennings, Megan Granata, Daniele Klein, Michael Wuest, William M Minbiole, Kevin Carnevale, Vincenzo Journal Article Germany Chembiochem. 2019 Dec 20. doi: 10.1002/cbic.201900698.