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The molecular signals sensed by VraTSR remain unknown. We investigated interactions of the membrane histidine kinase VraS with \u03b2\u2010lactams and glycopeptides. Photo\u2010crosslinking assays with a vancomycin\u2010derived and an ampicillin\u2010derived photoprobe revealed direct interaction of these two classes of antibiotics with full\u2010length VraS. Saturation transfer difference (STD) Nuclear Magnetic Resonance experiments confirmed vancomycin, ampicillin and penicillin G binding to VraS, with the involvement of aryl protons from the antibiotics. STD NMR assays with truncated versions of VraS demonstrated that ampicillin and vancomycin bind to the membrane\u2010anchored N\u2010terminal region of VraS. In contrast, assays with membrane vesicles expressing only VraT or co\u2010expressing VraS\/VraT did not show covalent adduct formation between VraT and the vancomycin\u2010derived photoprobe. VraS p\u2010azido\u2010L\u2010phenylalanine mutants demonstrated participation of the extracellular loop of VraS in \u03b2\u2010lactam binding. These results demonstrate that vancomycin and penicillins directly interact with VraS, an interaction that could be involved in activation of the cell wall stress stimulon and the mechanisms underlying antibiotic resistance.\n                  <\/jats:p>","DOI":"10.1002\/anie.202516608","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:47:58Z","timestamp":1764053278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Histidine Kinase VraS Interacts with Vancomycin and Penicillins Through its Membrane\u2010Anchored N\u2010terminal Domain"],"prefix":"10.1002","volume":"65","author":[{"given":"Melisa B.","family":"Antinori","sequence":"first","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR), CONICET\u2010UNR 27 de Febrero 210 bis  Rosario 2000 Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melani D.","family":"Peralta","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR), CONICET\u2010UNR 27 de Febrero 210 bis  Rosario 2000 Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8926-515X","authenticated-orcid":false,"given":"Irina P.","family":"Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR), CONICET\u2010UNR 27 de Febrero 210 bis  Rosario 2000 Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sychantha","sequence":"additional","affiliation":[{"name":"M.G. 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DeGroote Institute for Infectious Disease Research McMaster University  1280 Main St W Hamilton ON L8S 4L8 Canada"},{"name":"Department of Biochemistry and Biomedical Sciences McMaster University  1280 Main St W Hamilton ON L8S 4L8 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Rosario (IQUIR) CONICET\u2010UNR  27 de Febrero 210 bis Rosario 2000 Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0185-5751","authenticated-orcid":false,"given":"Sebastian A.","family":"Testero","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Rosario (IQUIR) CONICET\u2010UNR  27 de Febrero 210 bis Rosario 2000 Argentina"},{"name":"\u00c1rea Qu\u00edmica Org\u00e1nica, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas Universidad Nacional de Rosario (UNR)  Suipacha 570 Rosario 2000 Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9129-7131","authenticated-orcid":false,"given":"Gerard D.","family":"Wright","sequence":"additional","affiliation":[{"name":"M.G. 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