Evaluating the activity of the RNA polymerase inhibitor myxopyronin B against Staphylococcus aureus

• Published in: FEMS microbiology letters 2011-06, Vol.319 (2), p.176-179
• Main Authors: Moy, Terence I., Daniel, Anu, Hardy, Crystal, Jackson, Andrew, Rehrauer, Owen, Hwang, You Seok, Zou, Dong, Nguyen, Kien, Silverman, Jared A., Li, Qingyi, Murphy, Christopher
• Format: Article
• Language: English
• Subjects: Amino acids; Anti-Bacterial Agents - pharmacology; Antibiotics; Antimicrobial activity; Bacteriology; Binding sites; Biological and medical sciences; DNA-directed RNA polymerase; DNA-Directed RNA Polymerases - antagonists & inhibitors; DNA-Directed RNA Polymerases - genetics; DNA-Directed RNA Polymerases - metabolism; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Human serum albumin; Humans; Lactones - pharmacology; Microbial Sensitivity Tests; Microbiology; Minimum inhibitory concentration; Miscellaneous; Mutation; MyxB; protein binding; Protein folding; Proteins; resistance; Resistant mutant; Rifampin; RNA polymerase; Serum albumin; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Staphylococcus aureus - genetics; Transcription initiation
• ISSN: 0378-1097; 1574-6968
• DOI: 10.1111/j.1574-6968.2011.02282.x

Abstract Myxopyronin B (MyxB) binds to the switch region of RNA polymerase (RNAP) and inhibits transcriptional initiation. To evaluate the potential development of MyxB as a novel class of antibiotic, we characterized the antimicrobial activity of MyxB against Staphylococcus aureus. Spontaneous MyxB resistance in S. aureus occurred at a frequency of 8 × 10−8, similar to that of rifampin. The MyxB-;resistant mutants were found to be altered in single amino acid residues in the RNAP subunits that form the MyxB-;binding site. In the presence of human serum albumin, the MyxB minimum inhibitory concentration against S. aureus increased drastically (≥128-;fold) and 99.5% of MyxB was protein bound. Because of the high serum protein binding and resistance rate, we conclude that MyxB is not a viable starting point for antibiotic development.