Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure-activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.
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http://dx.doi.org/10.3762/bjoc.12.77 | DOI Listing |
J Med Chem
September 2020
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
The synthesis and biological evaluation of analogues of uridylpeptide antibiotics were described, and the molecular interaction between the 3'-hydroxy analogue of mureidomycin A (3'-hydroxymureidomycin A) and its target enzyme, phospho-MurNAc-pentapeptide transferase (MraY), was analyzed in detail. The structure-activity relationship (SAR) involving MraY inhibition suggests that the side chain at the urea-dipeptide moiety does not affect the MraY inhibition. However, the anti- activity is in great contrast and the urea-dipeptide motif is a key contributor.
View Article and Find Full Text PDFMolecules
November 2018
Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen, Germany.
Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived 'nucleoside antibiotics' target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products.
View Article and Find Full Text PDFBeilstein J Org Chem
June 2016
Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbruecken, Germany.
Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure-activity relationship (SAR) studies and first insights into muraymycin biosynthesis.
View Article and Find Full Text PDFJ Org Chem
July 2009
Centre for Chemical Biology, Richard Roberts Building, Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK.
A simple, two-step synthesis of amide derivatives of uracil polyoxin C (UPOC) methyl ester using the Ugi reaction is described. The four components employed in the Ugi reaction are 2',3'-isopropylidine-protected uridine-5'-aldehyde, 2,4-dimethoxybenzylamine, an isoxazolecarboxylic acid, and the convertible isonitrile N-(2-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)carbonitrile. Following the Ugi reaction, treatment with HCl in MeOH achieves deprotection of the isopropylidene group and the N-benzyl group and conversion of the isonitrile-derived amide (the Ugi product) into the corresponding methyl ester.
View Article and Find Full Text PDFJ Org Chem
May 2008
Centre for Chemical Biology, Richard Roberts Building, Department of Chemistry, University of Sheffield, Sheffield, UK.
Stereoselective syntheses of both the natural (C5'- S) and unnatural (C5'- R) diastereoisomers of uracil polyoxin C methyl ester have been developed. The key stereocontrolled step involves nucleophilic addition of trimethylsilyl cyanide to the appropriate chiral sulfinimine derived from 2',3'-protected 5'-formyluridine and (S)-(-)-tert-butanesulfinamide or (R)-(+)-tert-butanesulfinamide, respectively. A variety of substrate mimics designed to function as inhibitors of chitin synthase have been synthesized by conjugation of the methyl ester of uracil polyoxin C (UPOC) with activated isoxazole carboxylic acids.
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