Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection.

Abstract

A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10-8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10-8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL).

• Authors: Han-Qing Fang, Jie Zeng, Shou-Kai Wang, Xiao Wang, Fang Chen, Bo Li, Jie Liu, Zhen Jin, Ya-Hong Liu, You-Zhi Tang
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 27 Issue 3 (Jan 29 2022) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 35164203 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Diterpenes
• Polycyclic Compounds

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Diterpenes (therapeutic use)
• Drug Discovery
• Humans
• Methicillin-Resistant Staphylococcus aureus (isolation & purification)
• Mice
• Polycyclic Compounds (therapeutic use)
• Staphylococcal Infections (drug therapy)
• Surface Plasmon Resonance
• Pleuromutilins