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In this work, we applied RNAseq transcriptomics, Brx-roGFP2 biosensor measurements, and phenotype analyses to investigate the stress responses and defense mechanisms of\n            <jats:italic>S. aureus<\/jats:italic>\n            COL toward HOSCN stress. Based on the RNAseq transcriptome profile, HOSCN exerts strong thiol-specific oxidative, electrophile, and metal stress responses as well as protein damage in\n            <jats:italic>S. aureus<\/jats:italic>\n            , which is indicated by the strong induction of the HypR, TetR1, PerR, QsrR, MhqR, CstR, CsoR, CzrA, AgrA, HrcA, and CtsR regulons. Phenotype analyses of various mutants in HOSCN-responsive genes revealed that the HOSCN reductase MerA conferred the highest resistance toward HOSCN stress in\n            <jats:italic>S. aureus<\/jats:italic>\n            COL, whereas the QsrR and MhqR electrophile stress regulons do not contribute to protection. Brx-roGFP2 biosensor measurements and bacillithiol (BSH)-specific Western blot analyses revealed a strong oxidative shift of the bacillithiol redox potential (\n            <jats:italic>E<\/jats:italic>\n            <jats:sub>BSH<\/jats:sub>\n            ) and increased\n            <jats:italic>S<\/jats:italic>\n            -bacillithiolations in\n            <jats:italic>S. aureus<\/jats:italic>\n            , indicating that BSH is oxidized to bacillithiol disulfide (BSSB) under HOSCN stress. While the \u0394\n            <jats:italic>merA<\/jats:italic>\n            mutant was delayed in recovery of the reduced\n            <jats:italic>E<\/jats:italic>\n            <jats:sub>BSH<\/jats:sub>\n            , overproduction of MerA in the \u0394\n            <jats:italic>hypR<\/jats:italic>\n            mutant enabled faster recovery of\n            <jats:italic>E<\/jats:italic>\n            <jats:sub>BSH<\/jats:sub>\n            due to efficient HOSCN detoxification. Moreover, both MerA and BSH were shown to contribute to HOSCN resistance in growth assays. In summary, HOSCN provokes a thiol-specific oxidative, electrophile, and metal stress response, an oxidative shift in\n            <jats:italic>E<\/jats:italic>\n            <jats:sub>BSH<\/jats:sub>\n            and increased\n            <jats:italic>S<\/jats:italic>\n            -bacillithiolation in\n            <jats:italic>S. aureus<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              colonizes the skin and the airways but can also lead to life-threatening systemic and chronic infections. During colonization and phagocytosis by immune cells,\n              <jats:italic>S. aureus<\/jats:italic>\n              encounters the thiol-reactive oxidant HOSCN. The understanding of the adaptation mechanisms of\n              <jats:italic>S. aureus<\/jats:italic>\n              toward HOSCN stress is important to identify novel drug targets to combat multi-resistant\n              <jats:italic>S. aureus<\/jats:italic>\n              isolates. As a defense mechanism,\n              <jats:italic>S. aureus<\/jats:italic>\n              uses the flavin disulfide reductase MerA, which functions as HOSCN reductase and protects against HOSCN stress. Moreover, MerA homologs have conserved functions in HOSCN detoxification in other bacteria, including intestinal and respiratory pathogens. In this work, we studied the comprehensive thiol-reactive mode of action of HOSCN and its effect on the reversible shift of the\n              <jats:italic>E<\/jats:italic>\n              <jats:sub>BSH<\/jats:sub>\n              to discover new defense mechanisms against the neutrophil oxidant. These findings provide new leads for future drug design to fight the pathogen at the sites of colonization and infections.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03252-23","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T13:02:42Z","timestamp":1699275762000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["The neutrophil oxidant hypothiocyanous acid causes a thiol-specific stress response and an oxidative shift of the bacillithiol redox potential in\n            <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"11","author":[{"given":"Vu Van","family":"Loi","sequence":"first","affiliation":[{"name":"Institute of Biology-Microbiology, Freie Universit\u00e4t Berlin , Berlin, 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