- Expression and assay of an N-methyltransferase involved in the biosynthesis of a vancomycin group antibiotic
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An N-methyltransferase responsible for methylating the N-terminal leucine of a vancomycin group antibiotic has been expressed, and its activity assayed against a series of putative vancomycin precursors.
- O'Brien, Dominic P.,Kirkpatrick, Peter N.,O'Brien, Simon W.,Staroske, Thomas,Richardson, Timothy I.,Evans, David A.,Hopkinson, Andrew,Spencer, Jonathan B.,Williams, Dudley H.
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- Enzymatic glycosylation of vancomycin aglycon: Completion of a total synthesis of vancomycin and N- and C-terminus substituent effects of the aglycon substrate
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Studies on the further development of the sequential glycosylations of the vancomycin aglycon catalyzed by the glycosyltransferases GtfE and GtfD and the observation of unusual, perhaps unexpected, aglycon substrate substituent effects on the rate and eff
- Nakayama, Atsushi,Okano, Akinori,Feng, Yiqing,Collins, James C.,Collins, Karen C.,Walsh, Christopher T.,Boger, Dale L.
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supporting information
p. 3572 - 3575
(2014/07/21)
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- A systematic investigation of the synthetic utility of glycopeptide glycosyltransferases
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Glycosyltransferases involved in the biosynthesis of bacterial secondary metabolites may be useful for the generation of sugar-modified analogues of bioactive natural products. Some glycosyltransferases have relaxed substrate specificity, and it has been assumed that promiscuity is a feature of the class. As part of a program to explore the synthetic utility of these enzymes, we have analyzed the substrate selectivity of glycosyltransferases that attach similar 2-deoxy-L-sugars to glycopeptide aglycons of the vancomycin-type, using purified enzymes and chemically synthesized TDP β-2-deoxy-L-sugar analogues. We show that while some of these glycopeptide glycosyltransferases are promiscuous, others tolerate only minor modifications in the substrates they will handle. For example, the glycosyltransferases GtfC and GtfD, which transfer 4-epi-L-vancosamine and L-vancosamine to C-2 of the glucose unit of vancomycin pseudoaglycon and chloroorienticin B, respectively, show moderately relaxed donor substrate specificities for the glycosylation of their natural aglycons. In contrast, GtfA, a transferase attaching 4-epi-L-vancosamine to a benzylic position, only utilizes donors that are closely related to its natural TDP sugar substrate. Our data also show that the spectrum of donors utilized by a given enzyme can depend on whether the natural acceptor or an analogue is used, and that GtfD is the most versatile enzyme for the synthesis of vancomycin analogues.
- Oberthuer, Markus,Leimkuhler, Catherine,Kruger, Ryan G.,Lu, Wei,Walsh, Christopher T.,Kahne, Daniel
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p. 10747 - 10752
(2007/10/03)
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- Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria
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Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.
- Nicolaou,Cho, Suk Young,Hughes, Robert,Winssinger, Nicolas,Smethurst, Christian,Labischinski, Harald,Endermann, Rainer
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p. 3798 - 3823
(2007/10/03)
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- New selenium-based safety-catch linkers: Solid-phase semisynthesis of vancomycin
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Pro-allyl and pro-alloc linkers can be formed by alkylation or esterification of a selenium-bound resin (the example shown is for the formation of a polymer-bound pro-allyl derivative) and can be readily cleaved in excellent yields under mild conditions. The scope of the pro-allyl linker has been demonstrated with the solid-phase semisynthesis of vancomycin. Alloc = allyloxycarbonyl.
- Nicolaou,Winssinger, Nicolas,Hughes, Robert,Smethurst, Christopher,Cho, Suk Young
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p. 1084 - 1088
(2007/10/03)
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- Synthesis of Vancomycin from the Aglycon
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Vancomycin-resistant bacterial strains pose a serious threat to human health. Efforts to overcome vancomycin resistance by modifying the natural product have shown that the carbohydrates help modulate biological activity. To explore the mechanisms by which the carbohydrates function, it would be useful to have access to vancomycin derivatives containing different disaccharides. We now describe the synthesis of vancomycin from a readily available protected aglycon. This chemistry lays the groundwork for wide-ranging investigations of the roles of the carbohydrates in the biological activity of vancomycin. Moreover, in developing methods to glycosylate vancomcyin, we have extended the utility of the sulfoxide glycosylation reaction considerably by making it possible to use unhindered esters as neighboring groups. The chemistry we describe may also have implications for how to improve some other glycosylation methods.
- Thompson, Christopher,Ge, Min,Kahne, Daniel
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p. 1237 - 1244
(2007/10/03)
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- Total synthesis of vancomycin - Part 4: Attachment of the sugar moieties and completion of the synthesis
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The total synthesis of vancomycin (1, Figure 1) is described. The successful plan for this synthesis involves sequential and stereoselective coupling of vancomycin aglycon acceptor 6 and glycosyl donors, trichloroacetimidate 50 and glycosyl fluoride 27 (Scheme 8). Acceptor 6 was synthesized from vancomycin aglycon (2) (Scheme 1), which was derived both by total synthesis and by semisynthesis from vancomycin itself (1) (Scheme 2). The vancosamine derivative 27 was obtained by total synthesis (Scheme 3) while the glycosyl derivative 50 was prepared from glucal (46) (Scheme 6). A number of glycosidation model studies, carried out in order to establish the final route to vancomycin (1), are also described and so are a number of failed attempts to secure the target molecule (1).
- Nicolaou,Mitchell, Helen J.,Jain, Nareshkumar F.,Bando, Toshikazu,Hughes, Robert,Winssinger, Nicolas,Natarajan, Swaminathan,Koumbis, Alexandros E.
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p. 2648 - 2667
(2007/10/03)
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