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Methyltransferase Contingencies in the Pathway of Everninomicin D Antibiotics
and Analogues.
Authors Limbrick EM, Yñigez-Gutierrez AE, Dulin CC, Derewacz DK, Spraggins JM, McCulloch
KM, Iverson TM, Bachmann BO
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Chembiochem : a European journal of chemical biology
Year 2020
Date Published 7/1/2020
Volume : Pages Not Specified : Not Specified
PubMed Reference 32686210
Abstract Everninomicins are orthoester oligosaccharide antibiotics with potent activity
against multidrug-resistant bacterial pathogens. Everninomicins act by
disrupting ribosomal assembly in a distinct region in comparison to clinically
prescribed drugs. We employed microporous intergeneric conjugation with
Escherichia coli to manipulate Micromonospora for targeted gene-replacement
studies of multiple putative methyltransferases across the octasaccharide
scaffold of everninomicin effecting the A1 , C, F, and H rings. Analyses of
gene-replacement and genetic complementation mutants established the mutability
of the everninomicin scaffold through the generation of 12 previously unreported
analogues and, together with previous results, permitted assignment of the ten
methyltransferases required for everninomicin biosynthesis. The in vitro
activity of A1 - and H-ring-modifying methyltransferases demonstrated the
ability to catalyze late-stage modification of the scaffold on an A1 -ring
phenol and H-ring C-4' hydroxy moiety. Together these results establish the
potential of the everninomicin scaffold for modification through mutagenesis and
in vitro modification of advanced biosynthetic intermediates.


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