Discovery of Quaternized Pyridine-Thiazole-Pleuromutilin Derivatives with Broad-Spectrum Antibacterial and Potent Anti- MRSA Activity

The quaternization of compounds has emerged as a promising molecular design strategy for the development of antibiotics. Herein, we report the design, synthesis, antibacterial activities, and structure-activity relationships of a series of novel pleuromutilin derivatives containing a quaternary amine C-14 side chain. Most of these derivatives exhibited broad-spectrum antibacterial activity against the tested bacteria. 10b was the most effective antibacterial agent that displayed excellent antibacterial activity against five clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, remarkable antimycoplasma activity, rapid bactericidal effects, and a strong ability to damage bacterial biofilms. Further mechanistic studies indicated that 10b destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, 10b exhibited high survival protection and potent in vivo antibacterial efficacy (ED50 = 4.94 mg/kg) in a mouse model of systemic MRSA infection. These findings suggest that 10b is a promising candidate for the treatment of multi-drug-resistant infectious diseases, especially MRSA infections.

Automated summary

The design, synthesis, antibacterial activities, and structure-activity relationships of quaternary amine C-14 side chain-containing pleuromutilin derivatives were investigated. Most of these derivatives exhibited broad-spectrum antibacterial activity. Among them, 10b showed excellent antibacterial activity against MRSA and remarkable antimycoplasma activity, rapid bactericidal effects, and a strong ability to damage bacterial biofilms. Further mechanistic studies revealed that 10b exerted its antibacterial effects through the destruction of bacterial cell membranes.