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The nucleoid\u2010associated protein HU plays a significant role in bacterial DNA metabolism, supercoiling, and biofilm formation, making it a promising new target. In this work, structure\u2010based screening and identified cinnamic\u2010hydroxamic\u2010acid derivatives (CHADs) are conducted as HU inhibitors, with a minimum inhibitory concentration (MIC) of as low as\n                    <jats:bold>\n                      12\u00a0\u00b5g\u00a0mL\n                      <jats:sup>\u22121<\/jats:sup>\n                    <\/jats:bold>\n                    against a range of pathogenic bacteria. CHADs induce nucleoid deformation, preventing bacterial division and inhibiting growth. They exhibit low toxicity in mice and effectively treat infections in mouse models. Additionally, CHADs possess anti\u2010biofilm activity and supercoiling relaxation properties, countering bacterial stress responses to antibiotics. They suppress changes in gene expression required for optimal stress responses, resulting in synergistic effects with other antibiotics. Thus, CHADs represent a new class of antibiotics that inhibit bacterial stress responses by co\u2010targeting biofilm formation and DNA supercoiling.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509876","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T03:25:34Z","timestamp":1763781934000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cinnamic\u2010Hydroxamic\u2010Acid Derivatives Exhibit Antibiotic, Anti\u2010Biofilm, and Supercoiling Relaxation Properties by Targeting Bacterial Nucleoid\u2010Associated Protein HU"],"prefix":"10.1002","volume":"13","author":[{"given":"Huan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Jiaotong University 1st Affiliated Hospital Xi'an Shaanxi 710041 China"},{"name":"Key Laboratory of Surgical Critical Care and Life 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