Design, synthesis, and biological evaluation of novel pleuromutilin derivatives containing benzimidazoles as effective anti-MRSA agents. 2023

Qi-Wen Zhang, and Jie Ren, and Jia-Xun Lu, and Xiao-Ying Chen, and Xian-Jin He, and Qi Wang, and Zi-Dan Zhou, and Zhen Jin, and Zhen-Ling Zeng, and You-Zhi Tang
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.

A series of pleuromutilin derivatives containing benzimidazole were designed, synthesized, and evaluated for their antibacterial activities against Methicillin-resistant Staphylococcus aureus (MRSA) in this study. The in vitro antibacterial activities of the synthesized derivatives against four strains of S. aureus (MRSA ATCC 43300, S. aureus ATCC 29213, S. aureus 144, and S. aureus AD3) were determined by the broth dilution method. Among these derivatives, compound 58 exhibited superior in vitro antibacterial effect against MRSA (minimal inhibitory concentration [MIC] = 0.0625 μg/mL) than tiamulin (MIC = 0.5 μg/mL). Compound 58 possessed a faster bactericidal kinetic and a longer post-antibiotic effect time against MRSA than tiamulin. Meanwhile, at 8 μg/mL concentration, compound 58 did not display obviously cytotoxic effect on the RAW 264.7 cells. In addition, compound 58 (-2.04 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (-1.02 log10 CFU/mL) in reducing MRSA load in mice thigh infection model. In molecular docking study, compound 58 can successfully attach to the 50S ribosomal active site (the binding free energy is -8.11 kcal/mol). Therefore, compound 58 was a potential antibacterial candidate for combating MRSA infections.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D000097567 Pleuromutilins A tricyclic diterpene natural product isolated from Pleurotus mutilus (now referred to as Clitopilus scyphoides). Possesses modest antibacterial activity against primarily gram-positive bacterial organisms. Octahydro-5,8-dihydroxy-4,6,9,10- tetramethyl-6-vinyl-3a,9-propano-3aH-cyclopenta- cycloocten-1(4H)-one 8-glycolate,Pleuromutilin,Pleuromutilin Antibiotics,Drosophilin B
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000900 Anti-Bacterial Agents Substances that inhibit the growth or reproduction of BACTERIA. Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial
D001562 Benzimidazoles Compounds with a BENZENE fused to IMIDAZOLES.
D013211 Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications.
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055624 Methicillin-Resistant Staphylococcus aureus A strain of Staphylococcus aureus that is non-susceptible to the action of METHICILLIN. The mechanism of resistance usually involves modification of normal or the presence of acquired PENICILLIN BINDING PROTEINS. MRSA,Methicillin Resistant Staphylococcus aureus
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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