2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria

Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria

  • J Med Chem. 2024 Apr 25;67(8):6585-6609. doi: 10.1021/acs.jmedchem.4c00018.
Yinyong Zhang 1 2 3 4,  Dan Zhang 3 4,  Wenhao Zhao 3 4,  Hongyuan Li 3 4,  Zhengyu Lu 3 4,  Bin Guo 3 4,  Xin Meng 3 4,  Xianli Zhou 1 2 5,  Yushe Yang 3 4
Affiliations

Affiliations

  • 1 Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan China.
  • 2 Key Laboratory of Advanced Technologies of Material, Minister of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Affiliated Hospital, The Third People's Hospital of Chengdu, Southwest Jiaotong University, Chengdu 610000, Sichuan, China.
PMID: 38598362 DOI: 10.1021/acs.jmedchem.4c00018
Abstract

G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent Antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow Antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of Infection with multidrug-resistant P. aeruginosa, the potent in vivo Antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.

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