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 de… Show more
“…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.…”
Section: Discussionsupporting
confidence: 91%
“…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.…”
The mycobacterial phosphoglycosyltransferase WecA, which initiates arabinogalactan biosynthesis in , has been proposed as a target of the caprazamycin derivative CPZEN-45, a preclinical drug candidate for the treatment of tuberculosis. In this report, we describe the functional characterization of mycobacterial WecA and confirm the essentiality of its encoding gene in by demonstrating that the transcriptional silencing of is bactericidal and in macrophages. Silencing also conferred hypersensitivity of to the drug tunicamycin, confirming its target selectivity for WecA in whole cells. Simple radiometric assays performed with mycobacterial membranes and commercially available substrates allowed chemical validation of other putative WecA inhibitors and resolved their selectivity toward WecA versus another attractive cell wall target, translocase I, which catalyzes the first membrane step in the biosynthesis of peptidoglycan. These assays and the mutant strain described herein will be useful for identifying potential antitubercular leads by screening chemical libraries for novel WecA inhibitors.
“…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.…”
Section: Discussionsupporting
confidence: 91%
“…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.…”
The mycobacterial phosphoglycosyltransferase WecA, which initiates arabinogalactan biosynthesis in , has been proposed as a target of the caprazamycin derivative CPZEN-45, a preclinical drug candidate for the treatment of tuberculosis. In this report, we describe the functional characterization of mycobacterial WecA and confirm the essentiality of its encoding gene in by demonstrating that the transcriptional silencing of is bactericidal and in macrophages. Silencing also conferred hypersensitivity of to the drug tunicamycin, confirming its target selectivity for WecA in whole cells. Simple radiometric assays performed with mycobacterial membranes and commercially available substrates allowed chemical validation of other putative WecA inhibitors and resolved their selectivity toward WecA versus another attractive cell wall target, translocase I, which catalyzes the first membrane step in the biosynthesis of peptidoglycan. These assays and the mutant strain described herein will be useful for identifying potential antitubercular leads by screening chemical libraries for novel WecA inhibitors.
“…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].…”
Section: Inhibition Of Other Bacterial Phospho-nucleotide Transferasementioning
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“…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.…”
Section: Nucleoside Natural Product Inhibitors Of Mray and Related Enmentioning
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