病原伯克霍尔德氏菌通过膜脂重排产生的格拉迪林与两性霉素 B 协同增效。

IF 5.1 1区 生物学 Q1 MICROBIOLOGY mBio Pub Date : 2024-11-13 Epub Date: 2024-10-18 DOI:10.1128/mbio.02611-24
Claudia Simm, Tzong-Hsien Lee, Harshini Weerasinghe, Dean Walsh, Ioanna T Nakou, Madhu Shankar, Wai Chung Tse, Yu Zhang, Rebecca Inman, Roger J Mulder, Freya Harrison, Marie-Isabel Aguilar, Gregory L Challis, Ana Traven
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引用次数: 0

摘要

两性霉素 B(AmpB)是一种有效但有毒的抗真菌药物。因此,改善其活性/毒性关系很有意义。AmpB 通过两种拟议的机制破坏真菌膜:麦角甾醇从膜中螯合和孔隙形成。这两种机制是否同时起作用以及如何增强它们的作用仍有待充分了解。在这里,我们报告了一种由伯克霍尔德氏菌(Burkholderia gladioli)产生的多酮类抗生素--格拉迪林(gladiolin),它是 AmpB 的强效增效剂,并对隐球菌和念珠菌(包括耐药念珠菌)具有协同作用。Gladiolin 还能与 AmpB 协同对抗耐药真菌生物膜,同时对哺乳动物不产生细胞毒性。为了解释协同作用的机理,我们发现剑兰黄素通过一种以前未报道过的多酮类化合物结合模式与膜相互作用。此外,剑兰黄酮还能调节 AmpB 与脂质的结合,与单独使用 AmpB 相比,剑兰黄酮能导致更快、更明显的脂质重排,包括与麦角甾醇提取一致的膜变薄、增厚区域、孔隙形成以及膜破坏加剧。这些生物物理数据证明了龟甲素和 AmpB 在膜界面上的功能性相互作用。这些数据进一步表明,所提出的两种 AmpB 机制(麦角甾醇螯合和孔隙形成)共同作用于膜破坏,而甘菊黄素通过增强这两种机制而产生协同效应。总之,我们的研究结果揭示了AmpB的作用机制,并将剑兰黄素描述为一种AmpB增效剂,显示出一种不同于其抗生素活性的抗真菌机制。我们揭示了膜上的协同机制,并为改善 AmpB 活性/毒性关系的增效策略提供了见解:两性霉素 B(AmpB)是临床使用的最古老的抗真菌药物之一。它是一种有效的治疗药物,但由于其真菌靶标(膜脂麦角固醇)与哺乳动物靶标(胆固醇)相似,因此存在毒性问题。改善其活性/毒性关系的一种策略是使用增效剂进行组合治疗,这样可以降低AmpB的治疗剂量。在此,我们报告了发现抗生素格拉乔林作为安普溴的增效剂,可用于抗击几种重点人类真菌病原体和真菌生物膜,且不会增加对哺乳动物细胞的毒性。我们的研究表明,甘菊黄素通过增加和加速膜损伤来增强 AmpB 的效力。我们的研究结果还表明,从膜中提取麦角固醇和孔隙形成这两种拟议的机制都会受到甘菊黄素的影响,从而为目前关于安培溴作用机制的争论提供了深入的见解。
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Gladiolin produced by pathogenic Burkholderia synergizes with amphotericin B through membrane lipid rearrangements.

Amphotericin B (AmpB) is an effective but toxic antifungal drug. Thus, improving its activity/toxicity relationship is of interest. AmpB disrupts fungal membranes by two proposed mechanisms: ergosterol sequestration from the membrane and pore formation. Whether these two mechanisms operate in conjunction and how they could be potentiated remains to be fully understood. Here, we report that gladiolin, a polyketide antibiotic produced by Burkholderia gladioli, is a strong potentiator of AmpB and acts synergistically against Cryptococcus and Candida species, including drug-resistant C. auris. Gladiolin also synergizes with AmpB against drug-resistant fungal biofilms, while exerting no mammalian cytotoxicity. To explain the mechanism of synergy, we show that gladiolin interacts with membranes via a previously unreported binding mode for polyketides. Moreover, gladiolin modulates lipid binding by AmpB and, in combination, causes faster and more pronounced lipid rearrangements relative to AmpB alone which include membrane thinning consistent with ergosterol extraction, areas of thickening, pore formation, and increased membrane destruction. These biophysical data provide evidence of a functional interaction between gladiolin and AmpB at the membrane interface. The data further indicate that the two proposed AmpB mechanisms (ergosterol sequestration and pore formation) act in conjunction to disrupt membranes, and that gladiolin synergizes by enhancing both mechanisms. Collectively, our findings shed light on AmpB's mechanism of action and characterize gladiolin as an AmpB potentiator, showing an antifungal mechanism distinct from its proposed antibiotic activity. We shed light on the synergistic mechanism at the membrane, and provide insights into potentiation strategies to improve AmpB's activity/toxicity relationship.

Importance: Amphotericin B (AmpB) is one of the oldest antifungal drugs in clinical use. It is an effective therapeutic, but it comes with toxicity issues due to the similarities between its fungal target (the membrane lipid ergosterol) and its mammalian counterpart (cholesterol). One strategy to improve its activity/toxicity relationship is by combinatorial therapy with potentiators, which would enable a lower therapeutic dose of AmpB. Here, we report on the discovery of the antibiotic gladiolin as a potentiator of AmpB against several priority human fungal pathogens and fungal biofilms, with no increased toxicity against mammalian cells. We show that gladiolin potentiates AmpB by increasing and accelerating membrane damage. Our findings also provide insights into the on-going debate about the mechanism of action of AmpB by indicating that both proposed mechanisms, extraction of ergosterol from membranes and pore formation, are potentiated by gladiolin.

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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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