Hybrid Molecules of Benzothiazole and Hydroxamic Acid as Dual-Acting Biofilm Inhibitors with Antibacterial Synergistic Effect against Pseudomonas aeruginosa Infections

  • J Med Chem. 2025 Mar 27;68(6):6210-6232. doi: 10.1021/acs.jmedchem.4c02517.
Zhen-Meng Zhang  1 ,  Si-Yu Zhao  1 ,  Wen-Qian Liu  1 ,  Xiao Wu  1 ,  Jie Tang  1 ,  Yu-Jie Li  1 ,  Xi-Bing Hu  1 ,  Ying-Bo Zhou  1 ,  Li-Xuan Dai  2 ,  Mei-Yan Huang  1 ,  Ping Lan  1 ,  Ping-Hua Sun  1  2 ,  Jun Xu  1 ,  Jun Liu  1 ,  Jun-Xia Zheng  1  2  3
Affiliations
  • 1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, 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. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, P. R. China.
PMID: 40080180 DOI: 10.1021/acs.jmedchem.4c02517
Abstract

The ubiquitous opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa) causes biofilm-associated drug-resistant infections that often lead to treatment failure. Targeting the bacterium's quorum sensing (QS) and iron homeostasis presents a promising strategy to combat biofilm formation. This study synthesized benzothiazole-conjugated hydroxamic acid derivatives as dual-acting biofilm inhibitors, and compound JH21 was identified as the hit compound with potent submicromolar biofilm inhibitory activity (IC50 = 0.4 μM). Further mechanistic studies demonstrated not only that the production of virulence was decreased through mainly inhibiting QS system but also that JH21 competed for iron with the high-affinity siderophore pyoverdine, inducing iron deficiency and inhibiting biofilm. Moreover, JH21 significantly enhanced the efficacy of tobramycin and ciprofloxacin by 200- and 1000-fold, respectively, in a mouse wound Infection model. These results emphasized the feasibility of dual-acting biofilm inhibitors against resistant P. aeruginosa infections and the potential of JH21 as a novel Antibacterial synergist.

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