Myxopyronin

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.

References

• Irschik, Herbert (1983), Journal of Antibiotics, http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=antibiotics1968&cdvol=36&noissue=12&startpage=1651&lang=en&from=jnlabstract 

• Panek, James; Schaus, Jennifer V.; Lam, Kelvin; Palfreyman, Michael G.; Wuonola, Mark; Gustafson, Gary; Panek, James S. (1998), "Total Synthesis and Preliminary Antibacterial Evaluation of the RNA Polymerase Inhibitors (±)-Myxopyronin A and B", The Journal of Organic Chemistry 63 (7): 2401 

• Doundoulakis et al. (2004), Bioorganic & Medicinal Chemistry Letters Volume 14, Issue 22, 15 November 2004, Pages 5667-5672 

• Lira et al. (2007), Bioorganic & Medicinal Chemistry Letters Volume 17, Issue 24, 15 December 2007, Pages 6797-6800 

• Blue, Laura (17 October 2008), "A New Class of Antibiotics Could Offer Hope Against TB", Time, http://www.time.com/time/health/article/0,8599,1851375,00.html 

• Jayanta Mukhopadhyay, Kalyan Das, Sajida Ismail, David Koppstein, Minyoung Jang, Brian Hudson, Stefan Sarafianos, Steven Tuske, Jay Patel, Rolf Jansen, Herbert Irschik, Eddy Arnold & Richard H. Ebright (October 2008), "The RNA polymerase "switch region" is a target for inhibitors", Cell 135 (2): 295–307, doi:10.1016/j.cell.2008.09.033, PMC 2580802, PMID 18957204, http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2580802 

• Belogurov, G; et al. (advance online publication 22 October 2008), "Transcription inactivation through local refolding of the RNA polymerase structure", Nature 457 (7227): 332–5, doi:10.1038/nature07510, PMC 2628454, PMID 18946472 

• Mary X. Ho, Brian P. Hudson, Kalyan Das, Eddy Arnold & Richard H. Ebright (December 2009), "Structures of RNA polymerase-antibiotic complexes", Current opinion in structural biology 19 (6): 715–723, doi:10.1016/j.sbi.2009.10.010, PMC 2950656, PMID 19926275, http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2950656 

• Srivastava A, Talaue M, Liu S, Degen D, Ebright RY, Sineva E, Chakraborty A, Druzhinin SY, Chatterjee S, Mukhopadhyay J, Ebright YW, Zozula A, Shen J, Sengupta S, Niedfeldt RR, Xin C, Kaneko T, Irschik H, Jansen R, Donadio S, Connell N, Ebright RH (August 2011), "New target for inhibition of bacterial RNA polymerase: 'switch region'", Curr Opin Microbiol, doi:10.1016/j.mib.2011.07.030, PMID 21862392 

• Terence I. Moy, Anu Daniel, Crystal Hardy, Andrew Jackson, Owen Rehrauer, You Seok Hwang, Dong Zou, Kien Nguyen, Jared A. Silverman,Qingyi Li, Christopher Murphy (2011), "Evaluating the activity of the RNA polymerase inhibitor myxopyronin B against Staphylococcus aureus", FEMS Microbiology Letters 319 (2): 176–179, doi:10.1111/j.1574-6968.2011.02282.x