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.