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. As part of detailed structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5',6'--configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278576 | PMC |
| http://dx.doi.org/10.3390/molecules23112868 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A Sub-Micromolar MraY Inhibitor with an Aminoribosyl Uridine Structure and a (,)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling.
Molecules
March 2022
Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France.
New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers.
View Article and Find Full Text PDFDesign, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold.
Bioorg Med Chem
February 2022
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Muraymycins and caprazamycins are strong inhibitors of MraY, which is responsible for peptidoglycan biosynthesis. Although they are promising antibacterial agents with a novel mode of action, their chemical structures are rather complex. This study investigated the simplification of these natural products by structure-based drug design, synthesis, and biological evaluation.
View Article and Find Full Text PDFEnzymatic C-H Functionalization of l-Arg and l-Leu in Nonribosomally Derived Peptidyl Natural Products: A Tale of Two Oxidoreductases.
J Am Chem Soc
November 2021
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, United States.
Muraymycins are peptidyl nucleoside antibiotics that contain two C-modified amino acids, (2,3)-capreomycidine and (2,3)-β-OH-Leu. The former is also a component of chymostatins, which are aldehyde-containing peptidic protease inhibitors that─like muraymycin─are derived from nonribosomal peptide synthetases (NRPSs). Using feeding experiments and in vitro characterization of 12 recombinant proteins, the biosynthetic mechanism for both nonproteinogenic amino acids is now defined.
View Article and Find Full Text PDFMerging Natural Products: Muraymycin-Sansanmycin Hybrid Structures as Novel Scaffolds for Potential Antibacterial Agents.
Chemistry
December 2020
Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123, Saarbrücken, Germany.
To overcome bacterial resistances, the need for novel antimicrobial agents is urgent. The class of so-called nucleoside antibiotics furnishes promising candidates for the development of new antibiotics, as these compounds block a clinically unexploited bacterial target: the integral membrane protein MraY, a key enzyme in cell wall (peptidoglycan) biosynthesis. Nucleoside antibiotics exhibit remarkable structural diversity besides their uridine-derived core motifs.
View Article and Find Full Text PDFSimplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores.
ChemMedChem
August 2020
Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived "nucleoside antibiotics" have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!