A Modular Approach to Phosphoglycosyltransferase Inhibitors Inspired by Nucleoside Antibiotics

Abstract

Phosphoglycosyl transferases (PGTs) represent “gatekeeper” enzymes in complex glycan assembly pathways by catalyzing transfer of a phosphosugar from an activated nucleotide diphosphosugar to a membrane-resident polyprenol phosphate. The unique structures of selected nucleoside antibiotics, such as tunicamycin and mureidomycin A, which are known to inhibit comparable biochemical transformations, are exploited as the foundation for the development of modular synthetic inhibitors of PGTs. Herein we present the design, synthesis, and biochemical evaluation of two readily manipulatable modular scaffolds as inhibitors of monotopic bacterial PGTs. Selected compounds show IC50 values down to the 40 μm range, thereby serving as lead compounds for future development of selective and effective inhibitors of diverse PGTs of biological and medicinal interest.

N -Acetylglucosamine-1-Phosphate Transferase, WecA, as a Validated Drug Target in Mycobacterium tuberculosis

“…This was further confirmed by our experiments with the capuramycin and tunicamycin derivatives SQ641 and X-J99620886, each of which varied in their inhibitory activities against WecA and translocase I by a factor of 10 3 (Fig. S6), in agreement with published data (46). However, a recent report by Mitachi et al (47) describes the synthesis of muraymycin D1 and its amides, which inhibit WecA and translocase I of M. tuberculosis with much closer IC 50 s: muraymycin D1 and muraymycin D1 amide exhibited ϳ60-fold higher activity against translocase I than against WecA, while muraymycin D1 diamide reached IC 50 s of 0.07 M and 0.0096 M for WecA and translocase I, respectively, reflecting an ϳ7-fold difference in inhibitory activity on these two enzymes.…”

“…Given the similarities between WecA and translocase I, the design of compounds targeting both enzymes would be a particularly attractive option. In this context, a number of uridine-containing natural antibiotics have already been shown to inhibit both enzymes, albeit differentially (35,46). This was further confirmed by our experiments with the capuramycin and tunicamycin derivatives SQ641 and X-J99620886, each of which varied in their inhibitory activities against WecA and translocase I by a factor of 10 3 (Fig.…”

Mechanism of action of nucleoside antibacterial natural product antibiotics

“…A further group of small 20-25 kDa phospho-sugar transferase enzymes utilising a UDP-di-N-acetyl-bacillosamine substrate are involved in N-glycoconjugate biosynthesis in Campylobacter jejuni [86]. Synthetic peptidyl-uridine inhibitors have been synthesised as inhibitors of C. jejuni PglC, with IC50 values in the range 40-250 µM [87].…”

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

“…The stereochemistry of the 2,3-diaminobutyric acid unit at C-2 was found to be important for both MraY inhibition and antibacterial activity, and meta-tyrosine was 180-fold more active for MraY inhibition than Ltyrosine in the N-terminal dipeptide [33]. Two new series of peptidyl-uridines whose structures are based upon mureidomycin A and tunicamycin have been synthesised as inhibitors of C. jejuni PglC, and selected compounds show IC50 values in the range 40-250 µM [35]. The biosynthetic pathway to both the pacidamycin [36][37][38] and caprazamycin [39] antibiotics has been elucidated, hence the use of biosynthetic engineering offers the possibility of generating modified uridyl peptide antibiotics via fermentation in the future.…”