Myxopyronin was first isolated in 1983 from a soil bacterium by Werner Kohl and Herbert Irschik at the Helmholtz Centre for Infection Research (former GBF).[1] A total synthesis of myxopyronin was first reported in 1998 by James S. Panek and co-workers.[5]
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.[6][7] Synthetic analogs of the natural myxopyronins have been synthesized at Anadys Pharmaceuticals and at Rutgers University.[8][9]
Terence I. Moy and co-workers at Cubist Pharmaceuticals 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.[10]
Chemical structures of myxopyronin A (left) and myxopyronin B (right)
^ abKohl, Werner; Irschik, H.; Reichenbach, H.; Höhle, G., Myxopyronin A und B - zwei neue Antibiotika aus Myxococcus fulvus Stamm Mx f50, vol. 1983, pp. 1656–1667
^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, PMC2580802, PMID18957204
^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): 2401–6, doi:10.1021/jo9721610
^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, PMC2950656, PMID19926275
^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, 14 (5): 532–43, doi:10.1016/j.mib.2011.07.030, PMC3196380, PMID21862392
^Doundoulakis, Thomas; Xiang, Alan X.; Lira, Ricardo; Agrios, Konstantinos A.; Webber, Stephen E.; Sisson, Wes; Aust, Robert M.; Shah, Amit M.; Showalter, Richard E.; Appleman, James R.; Simonsen, Klaus B. (2004). "Myxopyronin B analogs as inhibitors of RNA polymerase, synthesis and biological evaluation". Bioorganic & Medicinal Chemistry Letters. 14 (22): 5667–5672. doi:10.1016/j.bmcl.2004.08.045. PMID15482944.
^Lira, Ricardo; Xiang, Alan X.; Doundoulakis, Thomas; Biller, William T.; Agrios, Konstantinos A.; Simonsen, Klaus B.; Webber, Stephen E.; Sisson, Wes; Aust, Robert M.; Shah, Amit M.; Showalter, Richard E.; Banh, Virginia N.; Steffy, Kevin R.; Appleman, James R. (2007). "Syntheses of novel myxopyronin B analogs as potential inhibitors of bacterial RNA polymerase". Bioorganic & Medicinal Chemistry Letters. 17 (24): 6797–6800. doi:10.1016/j.bmcl.2007.10.017. PMID17980587.
^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, PMID21477256