Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

Stefan Koppermann, Zheng Cui, Patrick D. Fischer, Xiachang Wang, Jannine Ludwig, Jon S. Thorson, Steven G. Van Lanen, Christian Ducho

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 IC 50 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.

Original languageEnglish
Pages (from-to)779-784
Number of pages6
JournalChemMedChem
Volume13
Issue number8
DOIs
StatePublished - Apr 23 2018

Bibliographical note

Funding Information:
We thank the Deutsche Forschungsgemeinschaft (DFG, grant DU 1095/5-1, C.D.), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, the National Center for Advancing Translational Sciences (UL1TR001998, X.W., J.S.T.) and the National Institutes of Health (NIH, grant AI087849, Z.C., S.G.V.L.) for financial support. P.D.F. is grateful for a doctoral fellowship of the Fonds der Chemischen Industrie (FCI). We also thank Professor Seok-Yong Lee (Duke University Medical Center) for providing us with the plasmid for the overexpression of MraY from A. aeolicus.

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • activity assays
  • antibiotics
  • natural products
  • nucleosides
  • structure–activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics (all)
  • Organic Chemistry

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