Mechanistic Analysis of Muraymycin Analogues: A Guide to the Design of MraY Inhibitors

Abstract

The systematic structure-activity relationship (SAR) of the muraymycins (MRYs) using an Ugi four-component reaction (U4CR) was investigated. The impact of the lipophilic substituent on antibacterial activity was significant, and the analogues 8 and 9 having a lipophilic side chain exhibited good activity against a range of Gram-positive bacterial pathogens, including MRSA and VRE. Further investigation of compounds 8 and 9 revealed these analogues to be selective inhibitors of the MraY transferase and nontoxic to HepG2 cells. The SAR of the accessory urea-peptide moiety indicated that it could be simplified. Our SAR study of the MRYs suggests a probable mechanism for inhibition of the MraY, where the inner moiety of the urea-dipeptide motif interacts with the carbohydrate recognition domain in the cytoplasmic loop 5. The predicted binding model would provide further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial "lead" compounds based on MRYs.

Inhibition of phospho-MurNAc-pentapeptide translocase (MraY) by nucleoside natural product antibiotics, bacteriophage ϕX174 lysis protein E, and cationic antibacterial peptides

“…In contrast, the muraymycin analogues noted above were highly selective for MraY inhibition over E. coli WecA [23]. The action of CPZEN-45 will prompt further interest in the selective inhibition of WecA and TagO.…”

“…In recent years several studies have used synthetic chemistry to access analogues with higher chemical stability or altered antibacterial spectrum. with muraymycin D2 IC50 0.01 µM) and antibacterial activity [22], and that the cyclic epicapreomycidine amino acid could be replaced by arginine, lysine or ornithine residues [23]. Using L-arginine in place of epicapreomycidine, Takeoka have further shown that the Cterminal amino acid can be removed while retaining full MraY inhibition activity, and enhanced antimicrobial activity against strains of Pseudomonas, and that an analogue containing two L-arginine residues shows MIC 4-8 µg/ml against Pseudomonas strains [24].…”

Synthesis and Medicinal Chemistry of Muraymycins, Nucleoside Antibiotics

“…44) Although inhibitory activity of epi-MRY D2 (32) was weakened, it still showed potent inhibitory activity (IC 50 0.09 µM, K i 49 nM). As for the mode of inhibition, these compounds present a common behaviour with respect to the substrates of MraY: they were all competitive and noncompetitive inhibitors toward the nucleotide and the lipid substrates, respectively.…”

5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

“…A major difference between both modes of interaction is the positioning of The effect of introducing a hydrophobic moiety on an aminoribosyl scaffold has already been reported. 34,35 On the one hand, Dini et al 34 reported an interesting SAR study of aminoribosyl uridine derivatives lacking the hydroxyl group at C-3′ and bearing various substituents at C-5′. Their study showed that the introduction of a hydrophobic chain at C-5′ led to a five-to ten-fold increase of in vitro potency compared to that of the parent compound.…”

“…These results are in good agreement with a positioning of the inhibitors according to the mode A suggested by our docking experiments. On the other hand, Matsuda et al 35 reported the synthesis of muraymycins analogues with an elaborate urea-dipeptide motif introduced on an amino acid at the C-5′ position of an aminoribosyl uridine scaffold. Biological evaluation of several analogs differing in the hydrophobic chain introduced on this urea-dipeptide was also reported and showed that the presence of a long hydrophobic chain decreased the inhibitory activity by a factor 30, while the antibacterial activity was improved due to a better membrane penetration.…”