Freie Universität Berlin, Institute for Biology-Microbiology, Königin-Luise-Strasse 12-16, D-14195 Berlin, Germany.
Freie Universität Berlin, Institute for Biology-Microbiology, Königin-Luise-Strasse 12-16, D-14195 Berlin, Germany.
Free Radic Biol Med. 2018 Nov 20;128:84-96. doi: 10.1016/j.freeradbiomed.2018.02.018. Epub 2018 Feb 15.
Gram-negative bacteria utilize glutathione (GSH) as their major LMW thiol. However, most Gram-positive bacteria do not encode enzymes for GSH biosynthesis and produce instead alternative LMW thiols, such as bacillithiol (BSH) and mycothiol (MSH). BSH is utilized by Firmicutes and MSH is the major LMW thiol of Actinomycetes. LMW thiols are required to maintain the reduced state of the cytoplasm, but are also involved in virulence mechanisms in human pathogens, such as Staphylococcus aureus, Mycobacterium tuberculosis, Streptococcus pneumoniae, Salmonella enterica subsp. Typhimurium and Listeria monocytogenes. Infection conditions often cause perturbations of the intrabacterial redox balance in pathogens, which is further affected under antibiotics treatments. During the last years, novel glutaredoxin-fused roGFP2 biosensors have been engineered in many eukaryotic organisms, including parasites, yeast, plants and human cells for dynamic live-imaging of the GSH redox potential in different compartments. Likewise bacterial roGFP2-based biosensors are now available to measure the dynamic changes in the GSH, BSH and MSH redox potentials in model and pathogenic Gram-negative and Gram-positive bacteria. In this review, we present an overview of novel functions of the bacterial LMW thiols GSH, MSH and BSH in pathogenic bacteria in virulence regulation. Moreover, recent results about the application of genetically encoded redox biosensors are summarized to study the mechanisms of host-pathogen interactions, persistence and antibiotics resistance. In particularly, we highlight recent biosensor results on the redox changes in the intracellular food-borne pathogen Salmonella Typhimurium as well as in the Gram-positive pathogens S. aureus and M. tuberculosis during infection conditions and under antibiotics treatments. These studies established a link between ROS and antibiotics resistance with the intracellular LMW thiol-redox potential. Future applications should be directed to compare the redox potentials among different clinical isolates of these pathogens in relation to their antibiotics resistance and to screen for new ROS-producing drugs as promising strategy to combat antimicrobial resistance.
革兰氏阴性菌利用谷胱甘肽 (GSH) 作为其主要的低分子量巯基化合物。然而，大多数革兰氏阳性菌不编码 GSH 生物合成所需的酶，而是产生替代的低分子量巯基化合物，如芽孢杆菌硫醇 (BSH) 和分枝杆菌硫醇 (MSH)。BSH 被厚壁菌门利用，MSH 是放线菌门的主要低分子量巯基化合物。低分子量巯基化合物是维持细胞质还原状态所必需的，但也参与了人类病原体的毒力机制，如金黄色葡萄球菌、结核分枝杆菌、肺炎链球菌、肠炎沙门氏菌亚种。鼠伤寒和李斯特菌。感染条件通常会导致病原体细胞内氧化还原平衡的波动，而在抗生素治疗下，这种波动会进一步受到影响。在过去的几年中，新型谷氧还蛋白融合 roGFP2 生物传感器已在许多真核生物中进行了工程设计，包括寄生虫、酵母、植物和人类细胞，用于在不同隔室中动态成像 GSH 氧化还原电势。同样，现在也有基于细菌 roGFP2 的生物传感器可用于测量模型和致病性革兰氏阴性和革兰氏阳性细菌中 GSH、BSH 和 MSH 氧化还原电势的动态变化。在这篇综述中，我们介绍了细菌低分子量巯基化合物 GSH、MSH 和 BSH 在致病性细菌毒力调节中的新功能。此外，还总结了近年来关于遗传编码氧化还原生物传感器应用的研究结果，以研究宿主-病原体相互作用、持久性和抗生素耐药性的机制。特别是，我们强调了最近关于食源性病原体沙门氏菌 Typhimurium 以及革兰氏阳性病原体金黄色葡萄球菌和结核分枝杆菌在感染条件下和抗生素治疗下细胞内氧化还原变化的生物传感器研究结果。这些研究建立了 ROS 和抗生素耐药性与细胞内低分子量巯基-氧化还原电势之间的联系。未来的应用应致力于比较这些病原体不同临床分离株之间的氧化还原电势与其抗生素耐药性的关系，并筛选新的 ROS 产生药物，作为对抗抗生素耐药性的有前途的策略。
