<br>Eeyarestatin 24 对 Sec 依赖性蛋白分泌和细菌 DNA 的双重作用,ACS Infectious Diseases

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Eeyarestatin 24 对 Sec 依赖性蛋白分泌和细菌 DNA 的双重作用
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2023-01-13 , DOI: 10.1021/acsinfecdis.2c00404
Ann-Britt Schäfer ₁ , Maurice Steenhuis ₂ , Kin Ki Jim _{3,

4} , Jolanda Neef ₅ , Sarah O'Keefe ₆ , Roger C Whitehead ₇ , Eileithyia Swanton ₆ , Biwen Wang ₈ , Sven Halbedel _{9,

10} , Stephen High ₆ , Jan Maarten van Dijl ₅ , Joen Luirink ₂ , Michaela Wenzel ₁

Affiliation

Division of Chemical Biology, Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
Molecular Microbiology, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers - Location Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.
Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, 1081 HZ Amsterdam, The Netherlands.
Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands.
School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, United Kingdom.
School of Chemistry, Faculty of Science and Engineering, University of Manchester, Manchester M13 9PL, United Kingdom.
Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands.
FG11 Division of Enteropathogenic Bacteria and Legionella, Robert Koch Institute, 38855 Wernigerode, Germany.
Institute for Medical Microbiology and Hospital Hygiene, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.

Eeyarestatin 24 (ES24) 是一种有前景的广谱活性新型抗生素。它与呋喃妥因 (NFT) 具有结构相似性，但似乎具有独特且新颖的机制：ES24 被发现可以抑制革兰氏阴性细菌中 SecYEG 介导的蛋白质转运和膜插入。然而，尚未探索可能的其他目标。此外，其对革兰氏阳性菌的活性明显更好，但其作用机制尚未得到研究。我们使用革兰氏阳性模型细菌枯草芽孢杆菌，通过转录组应激反应分析、表型测定和蛋白质分泌分析来研究 ES24 与 NFT 的作用模式，并将我们的发现与革兰氏阴性大肠杆菌进行比较。在这里，我们展示了枯草芽孢杆菌中 Sec 依赖性蛋白分泌的抑制，并另外提供了 DNA 损伤的证据，这可能是由 ES24 反应性衍生物的生成引起的。有趣的是，ES24 导致膜电位逐渐耗散，从而导致大肠杆菌中细胞因子蛋白的离域和随后的细胞伸长。然而，在枯草芽孢杆菌中没有观察到这些效应，从而表明ES24对于革兰氏阳性菌和革兰氏阴性菌表现出明显的机制差异。尽管 ES24 与 NFT 结构相似，但在我们的表型分析中却存在很大差异，这意味着它不具有 NFT 的广义大分子和结构损伤机制。重要的是，在斑马鱼胚胎肺炎球菌感染模型中，ES24 的体内表现优于 NFT。我们的结果表明，ES24 不仅抑制 Sec 易位子，而且还靶向细菌 DNA，以及革兰氏阴性细菌的细胞膜。

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Dual Action of Eeyarestatin 24 on Sec-Dependent Protein Secretion and Bacterial DNA

Eeyarestatin 24 (ES24) is a promising new antibiotic with broad-spectrum activity. It shares structural similarity with nitrofurantoin (NFT), yet appears to have a distinct and novel mechanism: ES24 was found to inhibit SecYEG-mediated protein transport and membrane insertion in Gram-negative bacteria. However, possible additional targets have not yet been explored. Moreover, its activity was notably better against Gram-positive bacteria, for which its mechanism of action had not yet been investigated. We have used transcriptomic stress response profiling, phenotypic assays, and protein secretion analyses to investigate the mode of action of ES24 in comparison with NFT using the Gram-positive model bacterium Bacillus subtilis and have compared our findings to Gram-negative Escherichia coli. Here, we show the inhibition of Sec-dependent protein secretion in B. subtilis and additionally provide evidence for DNA damage, probably caused by the generation of reactive derivatives of ES24. Interestingly, ES24 caused a gradual dissipation of the membrane potential, which led to delocalization of cytokinetic proteins and subsequent cell elongation in E. coli. However, none of those effects were observed in B. subtilis, thereby suggesting that ES24 displays distinct mechanistic differences with respect to Gram-positive and Gram-negative bacteria. Despite its structural similarity to NFT, ES24 profoundly differed in our phenotypic analysis, which implies that it does not share the NFT mechanism of generalized macromolecule and structural damage. Importantly, ES24 outperformed NFT in vivo in a zebrafish embryo pneumococcal infection model. Our results suggest that ES24 not only inhibits the Sec translocon, but also targets bacterial DNA and, in Gram-negative bacteria, the cell membrane.

更新日期：2023-01-13

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