ABSTRACT
BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) usually invalidate powerful antibiotics in the clinic. Pleuromutilin derivatives have been reported to possess antibacterial activity against MRSA. OBJECTIVE: The antibacterial activities against MRSA of a series of thirteen synthetic pleuromutilin derivatives were investigated through in vitro models. METHODS: A series of novel thioehter pleuromutilin derivatives incorporating various aromatic substituents into the C14 side chain have been reported. The in vitro antibacterial activities of these derivatives against MRSA and Escherichia coli were tested by the broth dilution method. RESULTS: Twelve pleuromutilin derivatives were designed, synthesized and evaluated for in vitro antibacterial activities against four Staphylococcus aureus strains. From structure-activity relationship studies, compound 11c was identified as promising compounds with the most potent in vitro antibacterial activity among the series (MIC = 0.0625-0.125 µg/ml) against Staphylococcus aureus strains. The binding of compound 11c to the 50s ribosome was investigated by molecular modeling. CONCLUSION: It was found that there is a reasonable correlation between the binding free energy and the antibacterial activity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Mercaptoethylamines/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Diterpenes/chemical synthesis , Diterpenes/chemistry , Diterpenes/pharmacology , Escherichia coli/drug effects , Mercaptoethylamines/chemical synthesis , Mercaptoethylamines/chemistry , Microbial Sensitivity Tests , Molecular Docking Simulation , Polycyclic Compounds , Ribosome Subunits, Large, Bacterial/chemistry , Staphylococcus aureus/drug effects , Structure-Activity Relationship , PleuromutilinsABSTRACT
We synthesized a series of novel thioether pleuromutilin derivatives incorporating 2-aminothiophenol moieties into the C14 side chain via acylation reactions under mild conditions. We evaluated the in-vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA. We conducted docking experiments to understand the possible mode of interactions between compounds 8, 9b, 11a and 50S ribosomal subunit. The docking results proved that there is a reasonable correlation between the binding free energy and the antibacterial activity. Compound 8 was evaluated for its in-vivo antibacterial activity and showed higher efficacy than tiamulin against MRSA in mouse infection model.