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FEMS Microbiol Lett. 2011 Jun;319(2):176-9. doi: 10.1111/j.1574-6968.2011.02282.x. Epub 2011 Apr 20.

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

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1
Cubist Pharmaceuticals Inc., Lexington, MA 02421, USA. terence.moy@cubist.com

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.

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