title: Evaluating the activity of the RNA polymerase inhibitor myxopyronin B against Staphylococcus aureus.
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.
authors.affiliation: Cubist Pharmaceuticals Inc., Lexington, MA 02421, USA. terence.moy@cubist.com
authors.forename: Terence I
authors.initials: TI
authors.lastname: Moy
authors.forename: Anu
authors.initials: A
authors.lastname: Daniel
authors.forename: Crystal
authors.initials: C
authors.lastname: Hardy
authors.forename: Andrew
authors.initials: A
authors.lastname: Jackson
authors.forename: Owen
authors.initials: O
authors.lastname: Rehrauer
authors.forename: You Seok
authors.initials: YS
authors.lastname: Hwang
authors.forename: Dong
authors.initials: D
authors.lastname: Zou
authors.forename: Kien
authors.initials: K
authors.lastname: Nguyen
authors.forename: Jared A
authors.initials: JA
authors.lastname: Silverman
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Li
authors.forename: Christopher
authors.initials: C
authors.lastname: Murphy
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007783:Lactones; C040323:myxopyronin B; D012321:DNA-Directed RNA Polymerases