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Here, we show that sub-MIC levels of metronidazole, amoxicillin, and ciprofloxacin potently induce dense\n                      <jats:italic toggle=\"yes\">H. pylori<\/jats:italic>\n                      biofilms. Through transcriptomic and genetic analyses, we identify the two-component system CrdRS as a central signaling hub that orchestrates this response via the bidirectional regulation of two ATP-binding cassette (ABC) transporters. Phosphorylated CrdR binds to AC-rich promoter motifs to directly activate\n                      <jats:italic toggle=\"yes\">plpA<\/jats:italic>\n                      , which encodes a substrate-binding protein that drives exopolysaccharide secretion and matrix assembly. Concomitantly, CrdR represses\n                      <jats:italic toggle=\"yes\">glnP<\/jats:italic>\n                      , which encodes an inner-membrane permease, thereby relieving transcriptional inhibition of the L-asparaginase gene\n                      <jats:italic toggle=\"yes\">ansB<\/jats:italic>\n                      . This derepression triggers aberrant reactive oxygen species (ROS) accumulation, which promotes oxidative stress-dependent biofilm maturation. Through phenotypic analysis of c\n                      <jats:italic toggle=\"yes\">rdRS<\/jats:italic>\n                      deletion mutants, phosphorylation-defective point mutants (CrdR\n                      <jats:sup>D53A<\/jats:sup>\n                      and CrdS\n                      <jats:sup>H173A<\/jats:sup>\n                      ), and exogenous hydrogen peroxide (H\u2082O\u2082) induction, we demonstrate that CrdRS is required for mediating antibiotic-induced stress responses in a manner genetically separable from ROS sensing. Collectively, our findings establish a dual-mechanism model in which CrdRS orchestrates antibiotic-induced biofilm formation by simultaneously controlling matrix production and intracellular ROS generation. Notably,\n                      <jats:italic toggle=\"yes\">glnP<\/jats:italic>\n                      expression was significantly lower in clinical multidrug-resistant isolates than in drug-sensitive ones, whereas\n                      <jats:italic toggle=\"yes\">plpA<\/jats:italic>\n                      showed the opposite trend. These findings provide a mechanistic foundation for developing CrdRS-targeted strategies to combat biofilm-associated\n                      <jats:italic toggle=\"yes\">H. pylori<\/jats:italic>\n                      infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00882-26","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:44:51Z","timestamp":1791211491000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["The two-component system CrdRS mediates sub-inhibitory antibiotic-induced biofilm formation in\n                    <i>Helicobacter pylori<\/i>\n                    via bidirectional regulation of transporters PlpA and GlnP"],"prefix":"10.1128","volume":"70","author":[{"given":"Wenxin","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0207yh398","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Microbiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0207yh398","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Microbiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University","place":["Jinan, 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