ABSTRACT
We report the discovery of the first bacterial ribosomal RNA (rRNA) synthesis inhibitor that has specific antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). A pharmacophore model was constructed on the basis of the protein-protein interaction between essential bacterial rRNA transcription factors NusB and NusE and employed for an in silico screen to identify potential leads. One compound, (E)-2-{[(3-ethynylphenyl)imino]methyl}-4-nitrophenol (MC4), demonstrated antimicrobial activity against a panel of S. aureus strains, including MRSA, without significant toxicity to mammalian cells. MC4 resulted in a decrease in the rRNA level in bacteria, and the target specificity of MC4 was confirmed at the molecular level. Results obtained from this work validated the bacterial rRNA transcription machinery as a novel antimicrobial target. This approach may be extended to other factors in rRNA transcription, and MC4 could be applied as a chemical probe to dissect the relationship among MRSA infection, MRSA growth rate, and rRNA synthesis, in addition to its therapeutic potential.
Subject(s)
Anti-Bacterial Agents/pharmacology , Hydrazones/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Nitrophenols/pharmacology , RNA, Ribosomal/antagonists & inhibitors , Anti-Bacterial Agents/adverse effects , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Computer Simulation , Drug Evaluation, Preclinical/methods , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/metabolism , Hydrazones/chemistry , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/growth & development , Microbial Sensitivity Tests , Nitrophenols/chemistry , Protein Conformation , RNA, Ribosomal/biosynthesis , RNA, Ribosomal/genetics , Ribosomal Proteins/chemistry , Ribosomal Proteins/metabolism , Transcription Factors/chemistry , Transcription Factors/metabolismABSTRACT
Staphylococcal pneumonia provoked by methicillin-resistant Staphylococcus aureus (MRSA) is a life-threatening infection in which α-toxin is an essential virulence factor. In this study, we investigate the influence of naringenin on α-toxin production and further assess its therapeutic performance in the treatment of staphylococcal pneumonia. Remarkably, the expression of α-toxin was significantly inhibited when the organism was treated with 16 µg/ml of naringenin. When studied in a mouse model of S. aureus pneumonia, naringenin could attenuate the symptoms of lung injury and inflammation in infected mice. These results suggest that naringenin is a promising agent for treatment of S. aureus infection.
Subject(s)
Bacterial Toxins/biosynthesis , Flavanones/therapeutic use , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Phytotherapy , Plant Extracts/therapeutic use , Pneumonia, Staphylococcal/drug therapy , Virulence Factors/biosynthesis , Animals , Cell Line , Citrus paradisi/chemistry , Female , Flavanones/pharmacology , Humans , Inflammation/drug therapy , Inflammation/microbiology , Solanum lycopersicum/chemistry , Methicillin-Resistant Staphylococcus aureus/metabolism , Mice , Mice, Inbred C57BL , Plant Extracts/pharmacology , Pneumonia, Staphylococcal/microbiologyABSTRACT
In the present study, the antimicrobial activity of glycyrrhetinic acid (GA) against Staphylococcus aureus, and its influence on the production of S. aureus alpha-haemolysin (Hla) were investigated, along with the in vivo activity of GA against S. aureus-induced pneumonia. GA could not inhibit the growth of S. aureus, but the secretion of Hla by S. aureus was significantly inhibited by low concentrations of GA in a dose-dependent manner. Furthermore, in vivo data show that GA provides protection against staphylococcal pneumonia in a murine model system.
Subject(s)
Anti-Bacterial Agents/pharmacology , Glycyrrhetinic Acid/pharmacology , Pneumonia, Bacterial/prevention & control , Staphylococcal Infections/microbiology , Staphylococcal Infections/prevention & control , Animals , Cell Line, Tumor , Humans , Male , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Molecular Structure , Pneumonia, Bacterial/microbiology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Staphylococcus aureusABSTRACT
The present study aimed to evaluate the antimicrobial activity of peppermint oil against Staphylococcus aureus, and further investigate the influence of peppermint oil on S. aureus virulence-related exoprotein production. The data show that peppermint oil, which contained high contents of menthone, isomenthone, neomenthol, menthol, and menthyl acetate, was active against S. aureus with minimal inhibitory concentrations (MICs) ranging from 64-256 µg/mL, and the production of S. aureus exotoxins was decreased by subinhibitory concentrations of peppermint oil in a dose-dependent manner. The findings suggest that peppermint oil may potentially be used to aid in the treatment of S. aureus infections.