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.
Yang
Min
M
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Proctor
Mark R
MR
Bolam
David N
DN
Errey
James C
JC
Field
Robert A
RA
Gilbert
Harry J
HJ
Davis
Benjamin G
BG
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