MacDermott-Opeskin Hugo I, Wilson Katie A, O'Mara Megan L
Research School of Chemistry, College of Science, The Australian National University, Canberra, ACT 2601, Australia.
Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL A1C 5S7 Canada.
ACS Infect Dis. 2023 Apr 14;9(4):815-826. doi: 10.1021/acsinfecdis.2c00530. Epub 2023 Mar 15.
The Gram-negative pathogen is a primary contributor to nosocomial multi-drug-resistant (MDR) infections. To combat the rise of MDR infections, novel features of need to be considered for the development of new treatment options. One such feature is the preferential scavenging of exogenous lipids, including host-derived polyunsaturated fatty acids (PUFAs), for membrane phospholipid synthesis. These alterations in membrane composition impact both the lipid chemistry and the membrane biophysical properties. In this work we examine how antimicrobial peptides (AMPs) interact with the inner membranes of in the presence and absence of polyunsaturated phospholipids. Using coarse-grained molecular dynamics simulations of complex inner membrane models derived from lipidomes of bacteria grown in the presence and absence of PUFAs, we examine the impact of the adsorption of four prototypical AMPs (CAMEL, LL-37, pexiganan, and magainin-2) on the membrane biophysical properties. Our simulations reveal that the impact of AMP adsorption on the membrane biophysical properties was dependent on both the membrane composition and the specific AMP involved. Both lipid headgroup charge and tail unsaturation played important roles in driving the interactions that occurred both within the membrane and between the membrane and AMPs. The changes to the membrane biophysical properties also showed a complex relationship with the AMP's physical properties, such as AMP charge, chain length, and charge-to-mass ratio. Cumulatively, this work highlights the importance of studying AMPs using a complex membrane environment and provides insights into the mechanistic action of AMPs in polyunsaturated lipid-rich bacterial membranes.
革兰氏阴性病原体是医院获得性多重耐药（MDR）感染的主要促成因素。为应对MDR感染的增加，在开发新的治疗方案时需要考虑该病原体的新特性。其中一个特性是优先清除外源性脂质，包括宿主来源的多不饱和脂肪酸（PUFA），用于膜磷脂合成。膜组成的这些变化会影响脂质化学和膜生物物理性质。在这项工作中，我们研究了在存在和不存在多不饱和磷脂的情况下，抗菌肽（AMP）如何与该病原体的内膜相互作用。使用从在存在和不存在PUFA的情况下生长的细菌脂质组衍生的复杂内膜模型的粗粒度分子动力学模拟，我们研究了四种典型AMP（骆驼抗菌肽、LL-37、pexiganan和蛙皮素-2）的吸附对膜生物物理性质的影响。我们的模拟表明，AMP吸附对膜生物物理性质的影响取决于膜组成和所涉及的特定AMP。脂质头部基团电荷和尾部不饱和度在驱动膜内以及膜与AMP之间发生的相互作用中都起着重要作用。膜生物物理性质的变化也与AMP的物理性质，如AMP电荷、链长度和电荷质量比，呈现出复杂的关系。总的来说，这项工作突出了在复杂膜环境中研究AMP的重要性，并为AMP在富含多不饱和脂质的细菌膜中的作用机制提供了见解。
