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  3. Synthesis and antibacterial evaluations of novel vancomycin analogues targeting bacteria membrane to combat Gram-negative infections

Synthesis and antibacterial evaluations of novel vancomycin analogues targeting bacteria membrane to combat Gram-negative infections

  • Eur J Med Chem. 2025 May 5:289:117483. doi: 10.1016/j.ejmech.2025.117483.
Tao Li 1,  Ruixue Zhang 1,  Hongzhi Gong 1,  Ziyi Tang 2,  Xinyu Li 1,  Zhi Gong 1,  Mahesh Challa 1,  Cheng Zou 1,  Shao-Lin Zhang 3,  Jian Guo 4,  Yun He 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Shuitu Technology Development Zone, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China.
  • 2 Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, 266 Fangzheng Ave, Beibei, Chongqing, 400714, PR China; Chongqing Institute for Food and Drug Control, Chongqing, 401120, PR China.
  • 3 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Shuitu Technology Development Zone, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China. Electronic address: zhangsl@cqu.edu.cn.
  • 4 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Shuitu Technology Development Zone, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China. Electronic address: jian.guo@cqu.edu.cn.
  • 5 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Shuitu Technology Development Zone, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China; BayRay Innovation Center, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China. Electronic address: yun.he@cqu.edu.cn.
PMID: 40056801 DOI: 10.1016/j.ejmech.2025.117483
Abstract

Vancomycin is primarily used to treat severe infections caused by Gram-positive bacteria and is often considered as the last-resort therapy in the life-threatening situation. However, it is inherently ineffective against Gram-negative bacteria. Herein, we report the design, synthesis, and biological evaluation of novel vancomycin analogues incorporated with lipophilic cationic groups. Through structural optimization and structure-activity relationship (SAR) studies, we identified vancomycin analogue 18b, which exhibited remarkable Antibacterial activity against A. baumannii ATCC 17978, with a MIC of 8 μg/mL. In contrast, vancomycin showed no activity against this strain, even at concentration as high as 128 μg/mL. Further investigations revealed that 18b possesses rapid bactericidal properties, low toxicity, and a reduced propensity to induce Bacterial resistance. The exceptional Antibacterial performance of 18b is partially attributed to the presence of membrane-targeting, lipophilic piperazine cationic groups. In a mouse model infected with A. baumannii ATCC 17978, 18b exhibited excellent efficacy at a dose of 20 mg/kg, while no toxicity was observed. These findings highlight 18b as a promising candidate for further development in the fight against Gram-negative Bacterial infections.

Keywords

Gram-negative bacteria; Membrane disruption; Vancomycin.

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