Chemistry:Myxopyronin
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]
References
- ↑ 1.0 1.1 Kohl, Werner; Irschik, H.; Reichenbach, H.; Höhle, G., Myxopyronin A und B - zwei neue Antibiotika aus Myxococcus fulvus Stamm Mx f50, 1983, pp. 1656–1667
- ↑ 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, http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=antibiotics1968&cdvol=36&noissue=12&startpage=1651&lang=en&from=jnlabstract
- ↑ Jayanta Mukhopadhyay; Kalyan Das; Sajida Ismail; David Koppstein; Minyoung Jang; Brian Hudson; Stefan Sarafianos; Steven Tuske et al. (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, PMID 18957204
- ↑ 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
- ↑ 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, PMID 19926275
- ↑ "New target for inhibition of bacterial RNA polymerase: 'switch region'", Curr Opin Microbiol 14 (5): 532–43, August 2011, doi:10.1016/j.mib.2011.07.030, PMID 21862392
- ↑ Doundoulakis, Thomas; Xiang, Alan X.; Lira, Ricardo; Agrios, Konstantinos A.; Webber, Stephen E.; Sisson, Wes; Aust, Robert M.; Shah, Amit M. et al. (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.
- ↑ Lira, Ricardo; Xiang, Alan X.; Doundoulakis, Thomas; Biller, William T.; Agrios, Konstantinos A.; Simonsen, Klaus B.; Webber, Stephen E.; Sisson, Wes et al. (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.
- ↑ Terence I. Moy; Anu Daniel; Crystal Hardy; Andrew Jackson; Owen Rehrauer; You Seok Hwang; Dong Zou; Kien Nguyen et al. (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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