Discovery of Catechol-Benzothiazole Conjugates as Antibacterial Synergists against Pseudomonas aeruginosa by Inhibiting Biofilm Formation

  • J Med Chem. 2026 May 14;69(9):11258-11291. doi: 10.1021/acs.jmedchem.6c00428.
Ying-Bo Zhou  1 ,  Xiao Wu  1 ,  Yu-Jie Li  1 ,  Si-Yu Zhao  1 ,  Xi-Bing Hu  1 ,  Zi-Yang Du  1 ,  Deng-Chao Lian  2 ,  Jing-Lin Xie  2 ,  Da-Xi He  1 ,  Ying Yang  1 ,  Jia-Hui Su  1 ,  Qing-Hui He  1 ,  You-Feng Zhu  3 ,  Yi-Qun Chang  1 ,  Ping Lan  1 ,  Ping-Hua Sun  1  2  3 ,  Xin-Hui Pan  2 ,  Jun-Xia Zheng  2  4 ,  Jun Liu  1
Affiliations
  • 1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou 510632, P. R. China.
  • 2. Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, P. R. China.
  • 3. Department of Critical Care Medicine, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, P. R. China.
  • 4. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, P. R. China.
PMID: 42077202 DOI: 10.1021/acs.jmedchem.6c00428
Abstract

The formation of Pseudomonas aeruginosa (P. aeruginosa) biofilm hinders the efficacy of Antibiotics, making clinical treatment challenging. Given that disrupting iron homeostasis represents a promising strategy for treating biofilm infections, a series of catechol-conjugated benzothiazole derivatives with iron-chelating properties was designed and synthesized. Among them, 4p was identified as the hit compound, demonstrating potent biofilm inhibition (IC50 = 0.27 μM). Mechanistic studies demonstrated that 4p attenuates biofilm formation by inhibiting heme oxygenase (HemO), impairing iron homeostasis, virulence factor production, and motility. Moreover, 4p synergized with ciprofloxacin (CIP) and tobramycin (Tob), enhancing their efficacy and delaying the development of resistance. Notably, 4p improved survival in Galleria mellonella (G. mellonella) and reduced Bacterial load by 2.10-2.11log10 CFU in mice wounds in vivo when combined with CIP and Tob. Collectively, these results highlight the potential of 4p as an Antibacterial synergist and a promising candidate for the treatment of P. aeruginosa infections.

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