Lipid A in outer membrane vesicles shields bacteria from polymyxins

IF 15.5 1区 医学 Q1 CELL BIOLOGY
Marie Burt, Georgia Angelidou, Christopher Nils Mais, Christian Preußer, Timo Glatter, Thomas Heimerl, Rüdiger Groß, Javier Serrania, Gowtham Boosarpu, Elke Pogge von Strandmann, Janis A. Müller, Gert Bange, Anke Becker, Mareike Lehmann, Danny Jonigk, Lavinia Neubert, Hinrich Freitag, Nicole Paczia, Bernd Schmeck, Anna Lena Jung
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Abstract

The continuous emergence of multidrug-resistant bacterial pathogens poses a major global healthcare challenge, with Klebsiella pneumoniae being a prominent threat. We conducted a comprehensive study on K. pneumoniae’s antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last-resort antibiotic. Our research demonstrates that OMVs protect bacteria from polymyxins. OMVs derived from Polymyxin B (PB)-stressed K. pneumoniae exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed Klebsiella. OMVs also shield bacteria from different bacterial families. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and Galleria mellonella. In all models, OMVs protected K. pneumoniae from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. The altered binding capacity of single OMVs from PB stressed K. pneumoniae could be linked to a reduction in the lipid A amount of their released vesicles. Although the amount of lipid A per vesicle is reduced, the overall increase in the number of vesicles results in an increased protection because the sum of lipid A and therefore PB binding sites have increased. This unravels the mechanism of the altered PB protective efficacy of OMVs from PB stressed K. pneumoniae compared to control OMVs. The lipid A-dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected Klebsiella from PB ex vivo and in vivo. The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross-protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug-resistant bacterial infections.

Abstract Image

外膜囊泡中的脂质 A 使细菌免受多粘菌素的侵害。
耐多药细菌病原体的不断出现对全球医疗保健构成了重大挑战,其中肺炎克雷伯氏菌是一个突出的威胁。我们对肺炎克雷伯菌的抗生素耐药机制进行了全面研究,重点是外膜囊泡和多粘菌素(一种最后的抗生素)。我们的研究表明,外膜囊泡能保护细菌免受多粘菌素的侵害。与未受多粘菌素影响的克雷伯氏菌的外膜囊泡相比,受多粘菌素 B(PB)影响的肺炎克雷伯氏菌的外膜囊泡由于囊泡化增加而显示出更强的保护效力。OMV 还能保护不同细菌科的细菌。我们使用精密切片肺片(PCLS)和鼠伤寒杆菌对这一点进行了体内外验证。在所有模型中,OMV 都能保护肺炎双球菌免受 PB 感染,并降低蛋白质水平上的相关应激反应。我们观察到 OMVs 的脂质组成在 PB 处理后发生了重大变化,从而影响了它们与 PB 的结合能力。肺炎克雷伯菌受到 PB 胁迫后,其单个 OMVs 的结合能力发生了改变,这可能与其释放的囊泡中的脂质 A 数量减少有关。虽然每个囊泡的脂质 A 量减少了,但由于脂质 A 的总和增加了,因此 PB 结合位点也增加了,囊泡数量的总体增加导致了保护能力的增强。这就揭示了与对照 OMV 相比,肺炎克氏菌受 PB 胁迫的 OMV 对 PB 的保护效力发生改变的机制。利用人工囊泡在体外证实了脂质 A 依赖性对 PB 的保护作用。此外,人工囊泡在体内外都成功地保护了克雷伯氏菌免受肺炎双球菌的感染。研究结果表明,OMV 可通过与多粘菌素结合,有效地充当诱饵,阻止抗生素与细胞表面的相互作用,从而起到保护细菌的作用。我们的研究结果为了解抗生素交叉保护的机制提供了宝贵的见解,并为开发新型治疗干预措施提供了潜在的途径,以应对不断升级的耐多药细菌感染的威胁。
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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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