Myxopyronin

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Myxopyronins (Myx) are a group of alpha-pyrone antibiotics, which are inhibitors of bacterial RNA polymerase (RNAP).[1][2] They target switch 1 and switch 2 of the RNAP "switch region".[3] Rifamycins and fidaxomicin also target RNAP, but target different sites in RNAP. Myxopyronins do not have cross-resistance with any other drugs so myxopyronins may be useful to address the growing problem of drug resistance in tuberculosis.[4] They also may be useful in treatment of methicillin-resistant Staphylococcus aureus (MRSA). They are in pre-clinical development and has not yet started clinical trials.

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)

References[edit]

  1. ^ a b Kohl, 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
  2. ^ Irschik, Herbert; Gerth, K.; Höfle, G.; Kohl, W.; Reichenbach, H. (1983), "The myxopyronins, new inhibitors of bacterial RNA synthesis from Myxococcus fulvus (Myxobacterales)", The Journal of Antibiotics, 36 (12): 1651–1658, doi:10.7164/antibiotics.36.1651, PMID 6420386
  3. ^ 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
  4. ^ Blue, Laura (17 October 2008), "A New Class of Antibiotics Could Offer Hope Against TB", Time, archived from the original on October 18, 2008
  5. ^ 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
  6. ^ 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
  7. ^ 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, PMC 3196380, PMID 21862392
  8. ^ 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. PMID 15482944.
  9. ^ 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. PMID 17980587.
  10. ^ 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, PMID 21477256
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