期刊
CHEMBIOCHEM
卷 21, 期 10, 页码 1510-1516出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201900698
关键词
antibacterial compounds; lipids; molecular dynamics; quaternary ammonium compounds; simulations
资金
- US National Institute of General Medical Sciences [R35 GM119426]
- Temple University
- Villanova University
- US National Science Foundation fellowship [DGE1144462]
- National Science Foundation [1625061]
- US Army Research Laboratory [W911NF-16-2-0189]
- National Institute of General Medical Sciences of the National Institutes of Health [S10OD020095]
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.
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