Clinically Relevant Bacterial Outer Membrane Models for Antibiotic Screening Applications,ACS Infectious Diseases

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Clinically Relevant Bacterial Outer Membrane Models for Antibiotic Screening Applications
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-07-06 , DOI: 10.1021/acsinfecdis.1c00217
Zeinab Mohamed ₁ , Jung-Ho Shin ₂ , Surajit Ghosh ₃ , Abhishek K Sharma ₃ , Ferra Pinnock ₃ , Samavi Bint E Naser Farnush ₃ , Tobias Dörr ₂ , Susan Daniel _{1,

3}

Affiliation

Antibiotic resistance is a growing global health concern that has been increasing in prevalence over the past few decades. In Gram-negative bacteria, the outer membrane is an additional barrier through which antibiotics must traverse to kill the bacterium. In addition, outer membrane features and properties, like membrane surface charge, lipopolysaccharide (LPS) length, and membrane porins, can be altered in response to antibiotics and therefore, further mediate resistance. Model membranes have been used to mimic bacterial membranes to study antibiotic-induced membrane changes but often lack the compositional complexity of the actual outer membrane. Here, we developed a surface-supported membrane platform using outer membrane vesicles (OMVs) from clinically relevant Gram-negative bacteria and use it to characterize membrane biophysical properties and investigate its interaction with antibacterial compounds. We demonstrate that this platform maintains critical features of outer membranes, like fluidity, while retaining complex membrane components, like OMPs and LPS, which are central to membrane-mediated antibiotic resistance. This platform offers a non-pathogenic, cell-free surface to study such phenomena that is compatible with advanced microscopy and surface characterization tools like quartz crystal microbalance. We confirm these OMV bilayers recapitulate membrane interactions (or lack thereof) with the antibiotic compounds polymyxin B, bacitracin, and vancomycin, validating their use as representative models for the bacterial surface. By forming OMV bilayers from different strains, we envision that this platform could be used to investigate underlying biophysical differences in outer membranes leading to resistance, to screen and identify membrane-active antibiotics, or for the development of phage technologies targeting a particular membrane surface component.

中文翻译：

用于抗生素筛选应用的临床相关细菌外膜模型

抗生素耐药性是一个日益严重的全球健康问题，在过去的几十年里，它的流行率一直在增加。在革兰氏阴性细菌中，外膜是一个额外的屏障，抗生素必须穿过它才能杀死细菌。此外，外膜特征和特性，如膜表面电荷、脂多糖 (LPS) 长度和膜孔蛋白，可以响应抗生素而改变，从而进一步介导耐药性。模型膜已被用于模拟细菌膜以研究抗生素引起的膜变化，但通常缺乏实际外膜的组成复杂性。这里，我们使用来自临床相关革兰氏阴性菌的外膜囊泡 (OMV) 开发了一个表面支持的膜平台，并用它来表征膜生物物理特性并研究其与抗菌化合物的相互作用。我们证明该平台保持了外膜的关键特征，如流动性，同时保留了复杂的膜成分，如 OMP 和 LPS，它们是膜介导的抗生素耐药性的核心。该平台提供非致病性、无细胞表面来研究此类现象，该表面与高级显微镜和表面表征工具（如石英晶体微量天平）兼容。我们证实这些 OMV 双层再现了与抗生素化合物多粘菌素 B、杆菌肽和万古霉素的膜相互作用（或缺乏相互作用），验证它们作为细菌表面代表性模型的用途。通过从不同菌株形成 OMV 双层，我们设想该平台可用于研究导致抗性的外膜中潜在的生物物理差异，筛选和识别膜活性抗生素，或用于开发针对特定膜表面成分的噬菌体技术.

更新日期：2021-09-10

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