Effects of benzothiazinone and ethambutol on the integrity of the corynebacterial cell envelope

Q1 Immunology and Microbiology
Fabian M. Meyer , Urska Repnik , Ekaterina Karnaukhova , Karin Schubert , Marc Bramkamp
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Abstract

The mycomembrane (MM) is a mycolic acid layer covering the surface of Mycobacteria and related species. This group includes important pathogens such as Mycobacterium tuberculosis, Corynebacterium diphtheriae, but also the biotechnologically important strain Corynebacterium glutamicum. Biosynthesis of the MM is an attractive target for antibiotic intervention. The first line anti-tuberculosis drug ethambutol (EMB) and the new drug candidate, benzothiazinone 043 (BTZ) interfere with the synthesis of the arabinogalactan (AG), which is a structural scaffold for covalently attached mycolic acids that form the inner leaflet of the MM. We previously showed that C. glutamicum cells treated with a sublethal concentration of EMB lose the integrity of the MM. In this study we examined the effects of BTZ on the cell envelope. Our work shows that BTZ efficiently blocks the apical growth machinery, however effects in combinatorial treatment with β-lactam antibiotics are only additive, not synergistic. Transmission electron microscopy (TEM) analysis revealed a distinct middle layer in the septum of control cells considered to be the inner leaflet of the MM covalently attached to the AG. This layer was not detectable in the septa of BTZ or EMB treated cells. In addition, we observed that EMB treated cells have a thicker and less electron dense peptidoglycan (PG). While EMB and BTZ both effectively block elongation growth, BTZ also strongly reduces septal cell wall synthesis, slowing down growth effectively. This renders BTZ treated cells likely more tolerant to antibiotics that act on growing bacteria.

苯并噻嗪酮和乙胺丁醇对棒状细菌包膜完整性的影响
菌膜是覆盖在分枝杆菌及其相关菌种表面的一层霉菌酸。这一组包括重要的病原体,如结核分枝杆菌、白喉棒状杆菌,以及生物技术上重要的菌株谷氨酸棒状杆菌。MM的生物合成是抗生素干预的一个有吸引力的目标。一线抗结核药物乙胺丁醇(EMB)和新的候选药物苯并噻嗪酮043 (BTZ)干扰阿拉伯半乳聚糖(AG)的合成,AG是一种结构支架,共价附着的霉菌酸形成MM的内部小叶。我们之前发现,用亚致死浓度的EMB处理的谷氨酸c细胞失去了MM的完整性。在本研究中,我们研究了BTZ对细胞包膜的影响。我们的研究表明,BTZ有效地阻断了根尖生长机制,但与β-内酰胺类抗生素联合治疗的效果只是相加性的,而不是协同性的。透射电镜(TEM)分析显示,在对照细胞的隔膜中有一个明显的中间层,被认为是与AG共价连接的MM的内小叶。BTZ或EMB处理细胞的隔膜中未检测到这一层。此外,我们观察到EMB处理的细胞具有更厚和更低电子密度的肽聚糖(PG)。虽然EMB和BTZ都能有效地阻断伸长生长,但BTZ还能强烈地减少间隔细胞壁的合成,有效地减缓生长。这使得BTZ处理的细胞可能对作用于生长细菌的抗生素更具耐受性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Surface
Cell Surface Immunology and Microbiology-Applied Microbiology and Biotechnology
CiteScore
6.10
自引率
0.00%
发文量
18
审稿时长
49 days
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