Antibiotic optimization via in vitro glycorandomization

  title={Antibiotic optimization via in vitro glycorandomization},
  author={Xun Fu and Christoph Albermann and Jiqing Jiang and Jianchun Liao and Changsheng Zhang and Jon S. Thorson},
  journal={Nature Biotechnology},
In nature, the attachment of sugars to small molecules is often used to mediate targeting, mechanism of action and/or pharmacology. As an alternative to pathway engineering or total synthesis, we report a useful method, in vitro glycorandomization (IVG), to diversify the glycosylation patterns of complex natural products. We have used flexible glycosyltransferases on nucleotide diphosphosugar (NDP-sugar) libraries to generate glycorandomized natural products and then applied chemoselective… 

Optimizing Antibiotics 111 Combinatorial chemoenzymatic strategies for in vitro glycoran-domization : Efforts toward antibiotic optimization

Findings suggest that the alteration of glycosylation patterns on secondary metabolites is a potential strategy for the generation of novel therapeutics.

Recombinant E. coli prototype strains for in vivo glycorandomization.

This work reports the construction of several recombinant E. coli prototype strains that allow the facile production of a range of small molecule glycosides and offers vast combinatorial potential by simple fermentation.

Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation.

A two-step strategy for disaccharide modulation using vancomycin as a model is reported. The strategy relies upon a glycosyltransferase-catalyzed 'reverse' reaction to enable the facile attachment of

Combining biocatalysis and chemoselective chemistries for glycopeptide antibiotics modification.

The impact of enzyme engineering upon natural product glycodiversification.

Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules.

This review covers the influence of Glycosylation upon various drug properties, the classes of glycosyl-conjugating enzymes amenable to glyco(randomization/diversification) schemes, approaches to the synthesis of required substrates and specific examples of glycorandomized libraries utilizing both wild-type and engineered enzymes.

Vancomycin analogues containing monosaccharides exhibit improved antibiotic activity: a combined one-pot enzymatic glycosylation and chemical diversification strategy.

A practical one-pot enzymatic approach with regeneration of cosubstrates to synthesize analogues of vancomycin that contain an N-alkyl glucosamine, which exhibited marked improvement in antibiotic activity against a vancomYcin-resistant strain of Enterococcus.

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization.

The glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycoside-induced cytotoxicity and Na+/K+-ATPase inhibition.



Altering the glycosylation pattern of bioactive compounds.

Chemoselective approaches to glycoprotein assembly.

Chemoselective approaches for assembling homogeneous glycoconjugates that attempt to reduce the barriers to their synthesis are summarized to make glycconjugate synthesis accessible to a broader community, thereby accelerating progress in glycobiology.

Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics.

The war against infectious bacteria is not over! Although vancomycin and glycopeptide antibiotics have provided a strong last line of defence against many drug-resistant bacteria, their overuse has

Vancomycin derivatives that inhibit peptidoglycan biosynthesis without binding D-Ala-D-Ala.

Results presented here show that carbohydrate-modified vancomycin compounds are effective against resistant bacteria because they interact directly with bacterial proteins involved in the transglycosylation step of cell wall biosynthesis, suggesting new strategies for designing glycopeptide antibiotics that overcome bacterial resistance.

Vancomycin assembly: nature's way.

The rules by which nature assembles the glycopeptid (vancomycin) and lipoglycopeptide (teicoplanin) antibiotics are becoming elucidated and verified: first amino acids are synthesized, then joined together and cross-linked.

Tandem action of glycosyltransferases in the maturation of vancomycin and teicoplanin aglycones: novel glycopeptides.

The glycopeptides vancomycin and teicoplanin are clinically important antibiotics. The carbohydrate portions of these molecules affect biological activity, and there is great interest in developing

Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria.

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 van comycin libraries are described.

Bioconjugation by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition.

The copper-catalyzed cycloaddition reaction between azides and alkynes functions efficiently in aqueous solution in the presence of a tris(triazolyl)amine ligand to make rapid and reliable covalent connections to micromolar concentrations of protein decorated with either of the reactive moieties.