Methyltransferase Contingencies in the Pathway of Everninomicin D Antibiotics and Analogues.

Autor: Limbrick EM; Department of Chemistry, Vanderbilt University, 7330 Stevenson Ctr, Nashville, TN 37235, USA.; Department of Chemistry, Mercer University, 1501 Mercer University Drive, Macon, GA 31207, USA., Yñigez-Gutierrez AE; Department of Chemistry, Vanderbilt University, 7330 Stevenson Ctr, Nashville, TN 37235, USA., Dulin CC; Department of Chemistry, Vanderbilt University, 7330 Stevenson Ctr, Nashville, TN 37235, USA., Derewacz DK; Department of Chemistry, Vanderbilt University, 7330 Stevenson Ctr, Nashville, TN 37235, USA., Spraggins JM; Department of Chemistry, Vanderbilt University, 7330 Stevenson Ctr, Nashville, TN 37235, USA.; Department of Biochemistry, Vanderbilt University School of Medicine, 607 Light Hall, Nashville, TN 37205, USA.; Mass Spectrometry Research Center, Vanderbilt University School of Medicine, 465 21st Ave S, Nashville, TN 37240, USA., McCulloch KM; Department of Pharmacology, Vanderbilt University 7124 MRBIII, 465 21st Ave S, Nashville, TN 37232, USA.; Department of Chemistry & Biochemistry, California State Polytechnic University, Pomona, 3801 West Temple Ave, Pomona, CA 91768, USA., Iverson TM; Department of Biochemistry, Vanderbilt University School of Medicine, 607 Light Hall, Nashville, TN 37205, USA.; Department of Pharmacology, Vanderbilt University 7124 MRBIII, 465 21st Ave S, Nashville, TN 37232, USA.; Vanderbilt Institute of Chemical Biology.; Vanderbilt Center for Structural Biology., Bachmann BO; Department of Chemistry, Vanderbilt University, 7330 Stevenson Ctr, Nashville, TN 37235, USA.; Department of Biochemistry, Vanderbilt University School of Medicine, 607 Light Hall, Nashville, TN 37205, USA.; Department of Pharmacology, Vanderbilt University 7124 MRBIII, 465 21st Ave S, Nashville, TN 37232, USA.; Vanderbilt Institute of Chemical Biology.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2020 Dec 01; Vol. 21 (23), pp. 3349-3358. Date of Electronic Publication: 2020 Sep 07.
DOI: 10.1002/cbic.202000305
Abstrakt: 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 A 1 , 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 A 1 - and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A 1 -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.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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