Outer Membranes of Polymyxin-Resistant Acinetobacter baumannii with Phosphoethanolamine-Modified Lipid A and Lipopolysaccharide Loss Display Different Atomic-Scale Interactions with Polymyxins.
Outer Membranes of Polymyxin-Resistant Acinetobacter baumannii with Phosphoethanolamine-Modified Lipid A and Lipopolysaccharide Loss Display Different Atomic-Scale Interactions with Polymyxins.
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DOI：
10.1021/acsinfecdis.0c00330
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发表时间：
2020-10-09
影响因子：
5.3
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Jiang X;Yang K;Han ML;Yuan B;Li J;Gong B;Velkov T;Schreiber F;Wang L;Li J
Resistance to the last-line polymyxins is increasingly reported in multidrug-resistant Gram-negative pathogens, including Acinetobacter baumannii which develops resistance via either lipid A modification or even lipopolysaccharides (LPS) loss in the outer membrane (OM). Considering these two different mechanisms, quantitative membrane lipidomics data were utilized to develop three OM models representing polymyxin-susceptible and -resistant A. baumannii strains. Through all-atom molecular simulations with enhanced sampling techniques, the effect of lipid A-pEtN modification and LPS loss on the action of colistin (i.e. polymyxin E) was examined for the first time, with a focus on the dynamics and energetics of colistin penetration into these OMs. Lipid A-pEtN modification improved the OM stability, impeding the penetration of colistin into the OM; this differed from the current literature that lipid A-pEtN modification confers resistance by diminishing the initial interaction with polymyxins. In contrast, LPS deficiency significantly reduced the negative charges on the OM surface, diminishing the binding of colistin. Moreover, both lipid A-pEtN modification and LPS loss also constituted colistin resistance through disturbing the conformational transitions of the colistin molecule. Collectively, atomic-scale interactions between polymyxins and different bacterial OMs are very different and the findings may facilitate the discovery of new-generation polymyxins against the Gram-negative ‘superbugs’. Polymyxins are a last-line therapy against MDR Gram-negative pathogens. Unfortunately, resistance to polymyxins can emerge via the remodeling of their outer membranes. Here, we employed all-atom molecular dynamics simulations to elucidate the mechanisms of polymyxin resistance in A. baumannii due to lipid A modification and loss of lipopolysaccharide.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
多粘菌素 B 松弛脂多糖双层，但强化磷脂双层
影响因子：
3.4
作者：
Fu, Lei;Wan, Mingwei;Fang, Weihai
通讯作者：
Fang, Weihai
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
5.2
作者：
Olaitan AO;Morand S;Rolain JM
通讯作者：
Rolain JM
DOI：
10.1016/j.ijantimicag.2016.06.023
发表时间：
2016-12-01
影响因子：
10.8
作者：
Baron, Sophie;Hadjadj, Linda;Olaitan, Abiola Olumuyiwa
通讯作者：
Olaitan, Abiola Olumuyiwa