Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America.
PLoS Genet. 2023 Jul 7;19(7):e1010834. doi: 10.1371/journal.pgen.1010834. eCollection 2023 Jul.
Sulfur is an indispensable element for bacterial proliferation. Prior studies demonstrated that the human pathogen Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a five-gene locus comprising a putative ABC-transporter and predicted γ-glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter operon the glutathione import system (gisABCD). Ggt is encoded within the gisBCD operon, and we show that the enzyme is capable of liberating glutamate using either GSH or GSSG as substrates, demonstrating it is a bona fide γ-glutamyl transpeptidase. We also determine that Ggt is expressed in the cytoplasm, representing only the second example of cytoplasmic Ggt localization, the other being Neisseria meningitidis. Bioinformatic analyses revealed that Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologs. However, homologous systems were not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH- and GSSG-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSSG in addition to GSH and promotes competition against other staphylococci commonly associated with the human microbiota.
硫是细菌增殖所必需的元素。先前的研究表明，人类病原体金黄色葡萄球菌利用谷胱甘肽（GSH）作为营养硫源；然而，GSH 获取机制尚不清楚。在这里，我们确定了一个包含假定 ABC 转运体和预测的γ-谷氨酰转肽酶（ggt）的五个基因座，该基因座可促进金黄色葡萄球菌在仅补充还原型或氧化型 GSH（GSSG）作为唯一营养硫源的培养基中增殖。基于这些表型，我们将该转运体操纵子命名为谷胱甘肽导入系统（gisABCD）。ggt 编码在 gisBCD 操纵子内，我们表明该酶能够使用 GSH 或 GSSG 作为底物释放谷氨酸，证明它是一种真正的γ-谷氨酰转肽酶。我们还确定 ggt 在细胞质中表达，这代表细胞质中 ggt 定位的第二个例子，另一个是脑膜炎奈瑟菌。生物信息学分析表明，与金黄色葡萄球菌密切相关的葡萄球菌属种编码 GisABCD-Ggt 同源物。然而，在表皮葡萄球菌中未检测到同源系统。因此，我们确定 GisABCD-Ggt 以 GSH 和 GSSG 依赖的方式为金黄色葡萄球菌提供了相对于表皮葡萄球菌的竞争优势。总的来说，这项研究描述了金黄色葡萄球菌中发现了一种营养硫获取系统，该系统除了 GSH 之外还靶向 GSSG，并促进了与人类微生物群中常见的其他葡萄球菌的竞争。
