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Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics

Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial...

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Autores principales: Wiegmann, Daniel, Koppermann, Stefan, Ducho, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320880/
https://www.ncbi.nlm.nih.gov/pubmed/30486316
http://dx.doi.org/10.3390/molecules23123085
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author Wiegmann, Daniel
Koppermann, Stefan
Ducho, Christian
author_facet Wiegmann, Daniel
Koppermann, Stefan
Ducho, Christian
author_sort Wiegmann, Daniel
collection PubMed
description Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one subclass of such naturally occurring MraY inhibitors. As part of structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report on novel derivatives with different attachment of one characteristic structural motif, i.e., the aminoribose moiety normally linked to the muraymycin glycyluridine core unit. Based on considerations derived from an X-ray co-crystal structure, we designed and synthesised muraymycin analogues having the aminoribose attached (via a linker) to either the glycyluridine amino group or to the uracil nucleobase. Reference compounds bearing the non-aminoribosylated linker units were also prepared. It was found that the novel aminoribosylated analogues were inactive as MraY inhibitors in vitro, but that the glycyluridine-modified reference compound retained most of the inhibitory potency relative to the unmodified parent muraymycin analogue. These results point to 6′-N-alkylated muraymycin analogues as a potential novel variation of the muraymycin scaffold for future SAR optimisation.
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spelling pubmed-63208802019-01-14 Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics Wiegmann, Daniel Koppermann, Stefan Ducho, Christian Molecules Article Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one subclass of such naturally occurring MraY inhibitors. As part of structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report on novel derivatives with different attachment of one characteristic structural motif, i.e., the aminoribose moiety normally linked to the muraymycin glycyluridine core unit. Based on considerations derived from an X-ray co-crystal structure, we designed and synthesised muraymycin analogues having the aminoribose attached (via a linker) to either the glycyluridine amino group or to the uracil nucleobase. Reference compounds bearing the non-aminoribosylated linker units were also prepared. It was found that the novel aminoribosylated analogues were inactive as MraY inhibitors in vitro, but that the glycyluridine-modified reference compound retained most of the inhibitory potency relative to the unmodified parent muraymycin analogue. These results point to 6′-N-alkylated muraymycin analogues as a potential novel variation of the muraymycin scaffold for future SAR optimisation. MDPI 2018-11-26 /pmc/articles/PMC6320880/ /pubmed/30486316 http://dx.doi.org/10.3390/molecules23123085 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wiegmann, Daniel
Koppermann, Stefan
Ducho, Christian
Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics
title Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics
title_full Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics
title_fullStr Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics
title_full_unstemmed Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics
title_short Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics
title_sort aminoribosylated analogues of muraymycin nucleoside antibiotics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320880/
https://www.ncbi.nlm.nih.gov/pubmed/30486316
http://dx.doi.org/10.3390/molecules23123085
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