2. Academic Validation
  3. Synthesis of peptidomimetics as antibiotic adjuvants for combination with aztreonam to combat MDR Pseudomonas aeruginosa

Synthesis of peptidomimetics as antibiotic adjuvants for combination with aztreonam to combat MDR Pseudomonas aeruginosa

  • Eur J Med Chem. 2023 Nov 15:260:115778. doi: 10.1016/j.ejmech.2023.115778.
Xican Ma 1,  Wei Guo 1,  Xi Zhu 1,  Zhiwen Li 1,  Yinghong Li 1,  Zhihao Guo 1,  Yanxiang Wang 1,  Jing Pang 1,  Min Yuan 2,  Zhenjun Li 2,  Xuefu You 1,  Xi Lu 3,  Yishuang Liu 4,  Danqing Song 5
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 State Key Laboratory for Infectious Diseases Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
  • 3 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: xilu@imb.pumc.edu.cn.
  • 4 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: liuys@imb.pumc.edu.cn.
  • 5 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: songdanqing@imb.pumc.edu.cn.
PMID: 37672933 DOI: 10.1016/j.ejmech.2023.115778
Abstract

Pseudomonas aeruginosa is one of the multipledrug-resistant (MDR) Gram-negative pathogens with few drugs available for treatment. Antibiotic adjuvant approach provides an alternative and complementary strategy. In this study, the stereo-structure-activity relationship of monobactams against MDR Gram-negative organisms was extended. Meanwhile, a series of novel peptidemimetic derivatives as Antibiotic adjuvants was synthesized and evaluated for their synergistic effects with aztreonam (AZT) against P. aeruginosa, using dipeptide PAβN as the lead. Among the analogues, compound 22j showed a significant synergistic effect against MDR P. aeruginosa in vitro and in vivo, presumably through the mechanism of affecting the permeability of outer membrane. Thus, we identified 22j as a novel peptidemimetic lead compound to potentiate the activity of AZT against MDR P. aeruginosa, which is worthy of further development as Antibiotic adjuvant candidates.

Keywords

Antibiotic adjuvant; Monobactam; Peptidomimetic; Pseudomonas aeruginosa; Synergistic effect.

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