Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

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 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.

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

“…The minimum inhibitory concentration (MIC) displays the relative antibiotic potency of AZM and each derivative against a common strain of bacteria ( Staphylococcus aureus) . The protocol used for the determination of the MIC was as previously described with minor modifications . Staphylococcus aureus subsp aureus Rosenbach (ATCC 6538) were grown in 5 mL of Bacto TM Tryptic Soy Broth medium for 16 hours at 37°C with shaking (250 rpm) when an aliquot was diluted X1000 into 4.5 mL of fresh medium and incubated until OD 600 reaching 0.4.…”

“…The protocol used for the determination of the MIC was as previously described with minor modifications. 24…”

Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

“…Both for potential applications and for more straightforward SAR studies, several simplified muraymycin analogues have been designed [34][35][36][37][38]. By comparison of different natural products and synthetic analogues with long alkyl side chains, it was shown that increased lipophilicity improves antibacterial activities (MIC values), but has only a minor effect on MraY inhibition [17,20,39,40]. This is probably owed to an improved cellular uptake of lipophilically decorated muraymycins.…”

“…This is probably owed to an improved cellular uptake of lipophilically decorated muraymycins. Through design of simplified analogues, the terminal urea dipeptide motif [40] as well as the 5 -O-aminoribosyl substituent [21,39] were identified to mediate key interactions in MraY inhibition. However, synthetically obtained 5 -defunctionalized ( 5 -deoxy') muraymycin C4 that was reported by our group [38] was found to still inhibit MraY in the nM range, even though most naturally occurring muramycins are MraY inhibitors with pM activities [39].…”

“…Through design of simplified analogues, the terminal urea dipeptide motif [40] as well as the 5 -O-aminoribosyl substituent [21,39] were identified to mediate key interactions in MraY inhibition. However, synthetically obtained 5 -defunctionalized ( 5 -deoxy') muraymycin C4 that was reported by our group [38] was found to still inhibit MraY in the nM range, even though most naturally occurring muramycins are MraY inhibitors with pM activities [39]. The replacement of (3S)-3-hydroxy-L-leucine with L-leucine resulted in a~25-fold loss of activity [41], but that implied that such simplified analogues may still be employed in SAR studies.…”