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.
|Number of pages||6|
|State||Published - Apr 23 2018|
Bibliographical noteFunding 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.
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
- activity assays
- natural products
- structure–activity relationships
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
- Pharmacology, Toxicology and Pharmaceutics (all)
- Organic Chemistry