Abstract
Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward their target protein, the bacterial membrane enzyme MraY. However, a structure-activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A-D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC50 values in the low-picomolar range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates.
Keywords:
activity assays; antibiotics; natural products; nucleosides; structure-activity relationships.
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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Crystallography, X-Ray
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Escherichia coli / drug effects*
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Escherichia coli / growth & development
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Escherichia coli Infections / drug therapy
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Escherichia coli Infections / microbiology
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Humans
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Molecular Docking Simulation
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Nucleosides / chemistry
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Nucleosides / pharmacology*
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Nucleotides / chemistry
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Nucleotides / pharmacology
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Peptides / chemistry
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Peptides / pharmacology*
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Staphylococcal Infections / drug therapy
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Staphylococcal Infections / microbiology
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / growth & development
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Structure-Activity Relationship
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Transferases (Other Substituted Phosphate Groups)
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Transferases / antagonists & inhibitors
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Transferases / chemistry
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Transferases / metabolism
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Urea / chemistry
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Urea / pharmacology
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Nucleosides
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Nucleotides
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Peptides
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muraymycin A1
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muraymycin C1
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muraymycin D1
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Urea
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Transferases
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Transferases (Other Substituted Phosphate Groups)
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mraY protein, Bacteria