2. Academic Validation
  3. Conformationally restricted pleuromutilins via a pyridinyl-amide tether bias peptidyl transferase center engagement enabling broad-spectrum potency against multidrug-resistant bacteria

Conformationally restricted pleuromutilins via a pyridinyl-amide tether bias peptidyl transferase center engagement enabling broad-spectrum potency against multidrug-resistant bacteria

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118316. doi: 10.1016/j.ejmech.2025.118316.
Lansheng Zhang 1,  Bingxing Zhang 2,  Lei Tian 2,  Juan Xia 3,  Mengzhou Wang 2,  Hongyu Chang 4,  Tao Hong 4,  Chengyuan Liang 5,  Ming Zhao 6
Affiliations

Affiliations

  • 1 Jiangsu Provincial Key Laboratory of Functional Substances in Traditional Chinese Medicine Formulae and Innovative Drug Discovery, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Lijiang Normal University, Lijiang, 674199, China.
  • 2 School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Xi'an Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Therapeutics Research, Xi'an, 710021, China.
  • 3 Jiangsu Provincial Key Laboratory of Functional Substances in Traditional Chinese Medicine Formulae and Innovative Drug Discovery, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Xi'an Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Therapeutics Research, Xi'an, 710021, China; Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, 524045, China.
  • 4 Xi'an Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Therapeutics Research, Xi'an, 710021, China; Shaanxi Guanjia High-Tech Biotechnology Co., Ltd., Xianyang, 713800, China.
  • 5 School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Xi'an Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Therapeutics Research, Xi'an, 710021, China. Electronic address: [email protected].
  • 6 Jiangsu Provincial Key Laboratory of Functional Substances in Traditional Chinese Medicine Formulae and Innovative Drug Discovery, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: [email protected].
PMID: 41187562 DOI: 10.1016/j.ejmech.2025.118316
Abstract

Drug-resistant bacteria are spreading at an alarming rate, yet the global antimicrobial pipeline remains largely dependent on structural modifications of existing Antibiotics. In this study, we explore innovative agents targeting multidrug-resistant (MDR) bacteria, drawing inspiration from recently approved pleuromutilins that feature a novel chemical scaffold. A conformational restriction strategy was employed, cyclizing the flexible C14 thioether-amide chain of valnemulin into a rigid pyridine-amide bridge. This modification preorganized the scaffold into its bioactive conformation at the ribosomal peptidyl transferase center (PTC). Guided by this design, we synthesized a series of amino acid-substituted pyridine-amide pleuromutilin derivatives and systematically assessed their Antibacterial properties. Among these, compound 14c exhibited broad-spectrum Antibacterial and pronounced antimycoplasmal activity, demonstrated rapid dose-dependent bactericidal effects, and showed low cytotoxicity. Mechanistic studies revealed that 14c binds to the PTC to inhibit protein synthesis, while also suppressing biofilm formation, disrupting preformed biofilms, and damaging Bacterial membranes. In a murine model of systemic methicillin-resistant Staphylococcus aureus (MRSA) Infection, treatment with 14c (15 mg/kg) resulted in a 90 % survival rate over seven days and significantly reduced Bacterial loads in multiple organs, outperforming valnemulin at equivalent doses. Overall, these findings indicate that conformationally restricted pleuromutilins with an intramolecular pyridinyl-amide tether bias PTC engagement, establishing 14c as a promising therapeutic candidate for combating MDR Bacterial infections.

Keywords

Amino acid-substitution; Antibiotics; Conformational restriction; Multidrug-resistant bacteria; Pleuromutilin.

Figures
Products