Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

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.