1. Evaluating the activity of the RNA polymerase inhibitor myxopyronin B against Staphylococcus aureus
- Author
-
Terence I, Moy, Anu, Daniel, Crystal, Hardy, Andrew, Jackson, Owen, Rehrauer, You Seok, Hwang, Dong, Zou, Kien, Nguyen, Jared A, Silverman, Qingyi, Li, and Christopher, Murphy
- Subjects
Lactones ,Staphylococcus aureus ,Mutation ,Drug Evaluation, Preclinical ,Humans ,DNA-Directed RNA Polymerases ,Microbial Sensitivity Tests ,Enzyme Inhibitors ,Staphylococcal Infections ,Anti-Bacterial Agents - 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.
- Published
- 2011