Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

Abstract

SummaryMuraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.

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

“…A promising target not yet addressed by clinically established classes of antibiotics is the bacterial enzyme MraY (translocase I) which mediates a key step in the intracellular stages of bacterial cell wall biosynthesis [4][5][6]. MraY catalyzes the first membrane-associated step in the cytosolic stage of peptidoglycan synthesis, i.e., the formation of the membrane-bound intermediate lipid I by reaction of UDP-MurNAc pentapeptide ('Park's nucleotide') with the isoprenoid membrane anchor undecaprenyl phosphate (Scheme 1) [7][8][9][10][11][12][13]. [18][19][20].…”

“…Nucleoside antibiotics are naturally produced secondary metabolites acting as MraY inhibitors. Several subclasses such as muraymycins, mureidomycins, tunicamycins, liposidomycins, and capuramycins have been reported [13][14][15][16]. Our research on nucleoside antibiotics mainly focusses on muraymycins which were isolated from Streptomyces sp.…”

“…Our research on nucleoside antibiotics mainly focusses on muraymycins which were isolated from Streptomyces sp. as a set of 19 structurally varying natural products [13,17]. Recently, several new members of this subclass have been reported [18].…”

Oligonucleotides with Cationic Backbone and Their Hybridization with DNA: Interplay of Base Pairing and Electrostatic Attraction

“…Aldehydes 3 and 4 were obtained by IBX oxidation of 5 and 6 in quantitative yields. On the basis of our previously reported syntheses of nucleosyl amino acids, [15] we applied as equenceo fW ittig-Horner olefination and asymmetric hydrogenation to introduce the amino acid motif. Wittig-Hornert ransformationsofaldehydes 3 and 4 with phosphonate 7 (see Supporting Information) furnished didehydro amino acids 8 and 9 in yields of 73 %a nd 68 %, respectively,w ith high stereoselectivities towardt he desired Z-isomers (93:7 and 91:9, respectively).…”

“…However,t he concomitantly formed E-isomers could not be fully removed, and thus, asymmetric hydrogenations were performed with the Z/E-mixtures. Hydrogenation of 8 and 9 in the presence of chiral Rh I catalysts (S,S)-and (R,R)-Me-DuPHOS-Rh [16] afforded the nucleosyl amino acid products 10 and 11 in yields of 54-92 %, with the major isomer (6'S or 6'R)d epending on the employed catalyst [(S,S)-catalyst for (6'S), (R,R)-catalyst for (6'R); for stereochemical assignments see Experimental Section].I nc ontrastt oo ur previous syntheses of nucleosyl amino acids, [15] the hydrogenation products were not obtained in diastereomericallyp ure form, but with diastereomeric ratios ranging from 85:15 to 95:5. HPLC purification of (S)-11 and (R)-11 gave the pure 6'-epimers (d.r.…”