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

Abstract

Muraymycins are a subclass of naturally occurring nucleoside antibiotics with promising antibacterial activity. They inhibit the bacterial enzyme translocase I (MraY), a clinically yet unexploited target mediating an essential intracellular step of bacterial peptidoglycan biosynthesis. Several structurally simplified muraymycin analogues have already been synthesized for structure-activity relationship (SAR) studies. We now report on novel derivatives with unprecedented variations in the nucleoside unit. For the synthesis of these new muraymycin analogues, we employed a bipartite approach facilitating the introduction of different nucleosyl amino acid motifs. This also included thymidine- and 5-fluorouridine-derived nucleoside core structures. Using an in vitro assay for MraY activity, it was found that the introduction of substituents in the 5-position of the pyrimidine nucleobase led to a significant loss of inhibitory activity towards MraY. The loss of nucleobase aromaticity (by reduction of the uracil C5-C6 double bond) resulted in a ca. tenfold decrease in inhibitory potency. In contrast, removal of the 2'-hydroxy group furnished retained activity, thus demonstrating that modifications of the ribose moiety might be well-tolerated. Overall, these new SAR insights will guide the future design of novel muraymycin analogues for their potential development towards antibacterial drug candidates.

Keywords: antibiotics; natural products; nucleoside analogues; structure–activity relationships.

Scheme 1

Reaction of Park’s nucleotide 1 with undecaprenyl phosphate 2 yielding lipid I 3, catalyzed by MraY (translocase I). UDP = uridine diphosphate, UMP = uridine monophosphate. The exact composition of the pentapeptide moiety varies among different bacteria [12].

Figure 1

Structures of selected naturally occurring muraymycins 4–7 [18,19,20].

Figure 2

X-ray co-crystal structure of MraY from Aquifex aeolicus in complex with muraymycin D2 7 (PDB 5CKR) [22,23]: protein-inhibitor interactions at the GlyU binding site (hydrocarbon scaffold of inhibitor 7 in light blue; orange arrow: well-defined uracil binding pocket; green arrow: ribose moiety of the uridine-derived GlyU unit showing no significant interactions of 2′-OH and 3′-OH).

Figure 3

Structures of previously reported 5′-deoxy muraymycin analogues 8–10 [24] and the previously reported protecting group-containing analogues 11 and 12 (PMB = p-methoxybenzyl, TBDMS = tert-butyldimethylsilyl) [34].

Scheme 2

Target structures 13–16 of this study and retrosynthetic strategy for 13–15.

Scheme 3

Stereocontrolled synthesis of (6′S)-configured nucleosyl amino acids 18–20.

Scheme 4

Synthesis of target structures 13–15.

Scheme 5

Synthesis of target structure 16.