Mitchell Natalie J, Seaton Pamela, Pokorny Antje
Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403, United States.
Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403, United States.
Biochim Biophys Acta. 2016 May;1858(5):988-94. doi: 10.1016/j.bbamem.2015.10.014. Epub 2015 Oct 26.
Iso- and anteiso-branched lipids are abundant in the cytoplasmic membranes of bacteria. Their function is assumed to be similar to that of unsaturated lipids in other organisms - to maintain the membrane in a fluid state. However, the presence of terminally branched membrane lipids is likely to impact other membrane properties as well. For instance, lipid acyl chain structure has been shown to influence the activity of antimicrobial peptides. Moreover, the development of resistance to antimicrobial agents in Staphylococcus aureus is accompanied by a shift in the fatty acid composition toward a higher fraction of anteiso-branched lipids. Little is known about how branched lipids and the location of the branch point affect the activity of membrane-active peptides. We hypothesized that bilayers containing lipids with low phase transition temperatures would tend to exclude peptides and be less susceptible to peptide-induced perturbation than those made from higher temperature melting lipids. To test this hypothesis, we synthesized a series of asymmetric phospholipids that only differ in the type of fatty acid esterified at the sn-2 position of the lipid glycerol backbone. We tested the influence of acyl chain structure on peptide activity by measuring the kinetics of release from dye-encapsulated lipid vesicles made from these synthetic lipids. The results were compared to those obtained using vesicles made from S. aureus and Staphylococcus sciuri membrane lipid extracts. Anteiso-branched phospholipids, which melt at very low temperatures, produced lipid vesicles that were only slightly less susceptible to peptide-induced dye release than those made from the iso-branched isomer. However, liposomes made from bacterial phospholipid extracts were generally much more resistant to peptide-induced perturbation than those made from any of the synthetic lipids. The results suggest that the increase in the fraction of anteiso-branched fatty acids in antibiotic-resistant strains of S. aureus is unlikely to be the sole factor responsible for the observed increased antibiotic resistance. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.
异分支和反异分支脂质在细菌的细胞质膜中含量丰富。据推测，它们的功能与其他生物体中不饱和脂质的功能相似——维持膜处于流体状态。然而，末端分支膜脂质的存在可能也会影响其他膜特性。例如，脂质酰基链结构已被证明会影响抗菌肽的活性。此外，金黄色葡萄球菌对抗菌剂耐药性的发展伴随着脂肪酸组成向更高比例的反异分支脂质转变。关于分支脂质和分支点的位置如何影响膜活性肽的活性，人们了解甚少。我们假设，与由较高温度熔化的脂质制成的双层膜相比，含有低相变温度脂质的双层膜倾向于排斥肽，并且对肽诱导的扰动不太敏感。为了验证这一假设，我们合成了一系列不对称磷脂，它们仅在脂质甘油主链sn-2位置酯化的脂肪酸类型上有所不同。我们通过测量由这些合成脂质制成的染料包封脂质体的释放动力学，来测试酰基链结构对肽活性的影响。将结果与使用金黄色葡萄球菌和松鼠葡萄球菌膜脂质提取物制成的脂质体所获得的结果进行比较。在非常低的温度下熔化的反异分支磷脂产生的脂质体，与由异分支异构体制成的脂质体相比，对肽诱导的染料释放仅略微不那么敏感。然而，由细菌磷脂提取物制成的脂质体通常比由任何一种合成脂质制成的脂质体对肽诱导的扰动更具抗性。结果表明，金黄色葡萄球菌耐药菌株中反异分支脂肪酸比例的增加不太可能是观察到的抗生素耐药性增加的唯一原因。本文是由卡尔·洛纳和凯·希尔珀特编辑的名为《抗菌肽》的特刊的一部分。
