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

Abstract

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. <b>10b</b> was the most effective antibacterial agent that displayed excellent antibacterial activity against five clinical methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) isolates, remarkable antimycoplasma activity, rapid bactericidal effects, and a strong ability to damage bacterial biofilms. Further mechanistic studies indicated that <b>10b</b> destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, <b>10b</b> exhibited high survival protection and potent <i>in vivo</i> antibacterial efficacy (ED₅₀ = 4.94 mg/kg) in a mouse model of systemic MRSA infection. These findings suggest that <b>10b</b> is a promising candidate for the treatment of multi-drug-resistant infectious diseases, especially MRSA infections.