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Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study
Author(s) -
Alkhalifa Saleh,
Jennings Megan C.,
Granata Daniele,
Klein Michael,
Wuest William M.,
Minbiole Kevin P. C.,
Carnevale Vincenzo
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900698
Subject(s) - membrane , amphiphile , phospholipid , ammonium , chemistry , biophysics , molecular dynamics , antimicrobial , intercalation (chemistry) , alkyl , combinatorial chemistry , bacteria , biochemistry , organic chemistry , biology , computational chemistry , copolymer , polymer , genetics
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 modeling 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 Escherichia coli and Staphylococcus 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 modeled.