Synthesis and evaluation of novel pleuromutilin derivatives targeting the 50S ribosomal subunit for antibacterial...

Area of Science:

• Medicinal Chemistry
• Microbiology
• Pharmacology

Background:

• Multidrug-resistant bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), pose a significant global health threat.
• There is a critical need for novel antibiotics without cross-resistance to existing drugs.

Purpose of the Study:

• To synthesize and evaluate a new class of pleuromutilin derivatives with substituted triazine moieties.
• To assess the antibacterial activity, resistance mitigation, and therapeutic potential of these novel compounds.

Main Methods:

• Synthesis of pleuromutilin derivatives containing substituted triazine.
• Antimicrobial activity testing against resistant bacterial strains.
• Docking model analysis and green fluorescent protein inhibition assay.
• Cytotoxicity, acute oral toxicity, and in vivo mouse systemic infection studies.

Main Results:

• Compound 6d, featuring a 4-dimethylamino-1,3,5-triazine side chain, demonstrated significant antimicrobial activity.
• 6d effectively mitigated antibiotic resistance.
• Docking and inhibition assays supported the high antibacterial potency of 6d.
• In vivo studies confirmed tolerable toxicity and promising therapeutic efficacy of 6d.

Conclusions:

• Novel pleuromutilin derivatives, particularly compound 6d, represent a promising new class of antibiotics.
• Compound 6d exhibits potent activity against multidrug-resistant bacteria and warrants further investigation for clinical application.