Myxopyronin (Myx) is an alpha-pyrone antibiotic, the first in a new class of inhibitors of bacterial RNA polymerase (RNAP) that target switch 1 and switch 2 of the RNAP "switch region." Rifamycin antibacterial agents, which are first-line treatments for tuberculosis, and lipiarmycin (fidaxomicin, Dificid) also target RNAP, but target different sites in RNAP. Myxopyronin does not have cross-resistance with rifamycins and lipiarmycin. Myxopyronin may be useful to address the growing problem of drug resistance in tuberculosis. It also may be useful in treatment of methicillin-resistant Staphylococcus aureus (MRSA). It is in pre-clinical development and has not yet started clinical trials.
Myxopyronin was first isolated in 1983 from a soil bacterium by Rolf Jansen and Herbert Irschik. A total synthesis of myxopyronin was first reported in 1998 by James S. Panek and co-workers. The target, the mechanism of action, and the structure of the complex of RNAP with myxopyronin were first reported in 2008 by Richard H. Ebright and co-workers. Novel analogs of myxopyronin have been synthesized at Anadys Pharmaceuticals (San Diego, CA) and at Rutgers University (Piscataway, NJ). Terence I. Moy and co-workers at Cubist Pharmaceuticals (Lexington, MA) have stated that, based on high resistance rate and high serum protein binding (comparable to rifamycins and lipiarmycin), the unmodified natural product myxopyronin B is not a viable starting point for antibiotic development.
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advance online publication 22 October 2008
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