Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics. (23rd March 2018)

• Record Type: Journal Article
• Authors: Koppermann, Stefan; Cui, Zheng; Fischer, Patrick D.; Wang, Xiachang; Ludwig, Jannine; Thorson, Jon S.; Van Lanen, Steven G.; Ducho, Christian
• Is Part Of: ChemMedChem. Volume 13:Number 8(2018)
• Page Start: 779
• Page End: 784
• Publication Date: 2018-03-23
• Subjects: activity assays -- antibiotics -- natural products -- nucleosides -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700793
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Natural products revisited : Naturally occurring muraymycin nucleoside antibiotics were studied for inhibitory activities toward their target protein, the bacterial membrane enzyme MraY. An in vitro MraY assay furnished SAR data on several representative muraymycins. These inhibitory potencies were correlated with antibacterial activities and to modelling data, thus providing detailed insights into the target interaction of muraymycins.