Cinnamic‐Hydroxamic‐Acid Derivatives Exhibit Antibiotic, Anti‐Biofilm, and Supercoiling Relaxation Properties by Targeting Bacterial Nucleoid‐Associated Protein HU
Finding novel compounds and drug targets is crucial for antibiotic development. The nucleoid-associated protein HU plays a significant role in bacterial DNA metabolism, supercoiling, and biofilm formation, making it a promising new target. In this work, structure-based screening and identified cinnamic-hydroxamic-acid derivatives (CHADs) are conducted as HU inhibitors, with a minimum inhibitory concentration (MIC) of as low as 12 µg mL<sup>-1</sup> 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-biofilm 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-targeting biofilm formation and DNA supercoiling.
Authors
- Huadong Liu (ORCID: https://orcid.org/0000-0002-8490-6170)
- Xiaoyan Zeng (ORCID: https://orcid.org/0000-0002-1107-7965)
- Shuai Yuan (ORCID: https://orcid.org/0000-0003-4037-3429)
- Chi Xu
- Zhenyue Hu
- Yingqi Xu (ORCID: https://orcid.org/0000-0001-6861-7355)
- Mingcai Li (ORCID: https://orcid.org/0000-0003-3910-6964)
- Mengzhe Li (ORCID: https://orcid.org/0000-0002-4390-8989)
- Stephen Matthews (ORCID: https://orcid.org/0000-0003-0676-0927)
- Zhaoping Xiong (ORCID: https://orcid.org/0000-0001-5041-9385)
- Xin Wang (ORCID: https://orcid.org/0000-0002-8694-1172)
- Bing Liu (ORCID: https://orcid.org/0000-0003-1670-6115)
- Wei Chen (ORCID: https://orcid.org/0000-0002-7499-9836)
- Yawen Wang (ORCID: https://orcid.org/0000-0002-1306-8931)
- Yahui Liu (ORCID: https://orcid.org/0000-0002-5983-0151)
- Zhonglin Wang (ORCID: https://orcid.org/0000-0001-6355-9651)
- Hongliang Wang (ORCID: https://orcid.org/0000-0001-9497-8509)
- Huan Chen (ORCID: https://orcid.org/0000-0002-5089-2719)
- Zuyi Yuan (ORCID: https://orcid.org/0000-0002-7341-6889)
- Yue Wu (ORCID: https://orcid.org/0000-0002-0084-2510)
- Yue Kang (ORCID: https://orcid.org/0000-0003-3244-8347)
- Yehuan Zheng
- Nan Qiao (ORCID: https://orcid.org/0009-0003-2495-8109)
Institutions
- Wuhan Institute of Virology (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Cloud Computing Center (CN)
- Health & Life (Taiwan) (TW)
- Imperial College London (GB)
- Huazhong University of Science and Technology (CN)
- Beijing University of Chemical Technology (CN)
- Hainan Medical University (CN)
- Xi'an Jiaotong University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1002/advs.202509876
- Citations
- 1
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China