Probing the breadth of macrolide glycosyltransferases: in vitro remodeling of a polyketide antibiotic creates active bacterial uptake and enhances potency.
The glycan portion of macrolide antibiotics modulates their efficacy. High-level expression of three macrolide GTs and kinetic analysis has revealed a highly selective synthetic "tool kit" with such plasticity that 12 glycan-modified macrolide antibiotics have been readily created. One of these (1-Gal) is enhanced over its parent oleandomycin (1) by "glycotargeting", allowing higher uptake through active internalization by virtue of the attachment of a glycan (Gal) not normally found on 1. Subsequent release of the targeting glycan by endogenous galactosidase activity releases 1.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Min
M
Yang
Mark R
MR
Proctor
David N
DN
Bolam
James C
JC
Errey
Robert A
RA
Field
Harry J
HJ
Gilbert
Benjamin G
BG
Davis
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001426:Bacterial Proteins; D004917:Erythromycin / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism*; D006031:Glycosylation; D006094:Gram-Positive Bacteria / Q000378:metabolism*; D048628:Ketolides / Q000378:metabolism* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009827:Oleandomycin / Q000378:metabolism; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D048628:Ketolides; D004917:Erythromycin; D005964:Glucosyltransferases; C519504:OleI protein, Streptomyces antibioticus; C075034:macrolide glycosyltransferase; D009827:Oleandomycin