Interactions of polymyxin B1 with the gram-negative inner membrane: A simulation study

多粘菌素 细菌外膜 多粘菌素B 脂多糖 革兰氏阴性菌 溶解 脂质A 细菌细胞结构 生物物理学 化学 内膜 细胞膜 抗生素 细菌 生物 生物化学 大肠杆菌 免疫学 遗传学 基因
作者
Dhanushka Weerakoon,Jan K. Marzinek,Peter J. Bond,Conrado Pedebos,Syma Khalid
出处
期刊:Biophysical Journal [Elsevier]
卷期号:122 (3): 371a-371a
标识
DOI:10.1016/j.bpj.2022.11.2043
摘要

The rise of drug resistant Gram-negative bacterial infections in recent decades has led to increased use of polymyxins, a class of antimicrobial peptides, as a ‘last resort’ treatment. In addition, the recent emergence of polymyxin-resistant strains threatens to bring about an era in which bacteria are resistant to all known antibiotics. It is thus necessary to develop new polymyxin-based antibiotics, but a lack of understanding of how polymyxins work at the molecular level may hinder such efforts. One question that remains open is how do polymyxins interact with the Gram-negative inner membrane to cause cell lysis? It has recently been suggested that polymyxins may target small quantities of the complex glycolipid lipopolysaccharide (LPS) that are present in the inner membrane prior to LPS transport to the outer membrane. In this work, we used a multiscale molecular dynamics (MD) approach including long-timescale, coarse-grained (CG) and atomistic simulations to investigate the interactions of polymyxin B1 (PMB1) with bacterial inner membrane models in the presence of small quantities of LPS. We observed that PMB1 is inserted into the inner membrane and localises at the LPS-phospholipid interface, sampling a wide range of interfacial environments. Our CG simulations also indicate that PMB1-LPS interactions are long-lived and numerous. In the presence of membrane proteins, a small number of PMB1 molecules were observed to form interactions with native inner membrane proteins, reducing the overall probability of PMB1 molecules remaining bound to LPS. Overall, this work indicates that PMB1 can target LPS molecules in the inner membrane, supporting recent hypotheses on its mode of action, while also providing new insights into the effect of membrane proteins upon PMB1-inner membrane interactions.
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