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

Authors


  • Editor: Jan-Ingmar Flock

Correspondence: Terence I. Moy, Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA. Tel.: +1 781 860 8799; fax: +1 781 861 1164; e-mail: 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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