Abstract
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 (e.g., with phosphoethanolamine [pEtN]) or even lipopolysaccharide (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, the 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 Gram-negative 'superbugs'.