GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation
Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assem...
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sg-ntu-dr.10356-1742292024-03-29T15:31:50Z GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation Zhang, Xiao-Lin Báti, Gábor Li, Chenyu Guo, Aoxin Yeo, Claresta Ding, Han Pal, Kumar Bhaskar Xu, Yuan Qiao, Yuan Liu, Xue-Wei School of Chemical and Biomedical Engineering Chemistry Medicine, Health and Life Sciences Anhydromuropeptide Glycosylation Glycosyl acceptor Enzymes Transglycosylase Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assembly. Existing TGase inhibitors like moenomycin and Lipid II analogues always occupy the TGase active sites; other strategies to interfere with proper PG elongation have not been widely exploited. Inspired by the natural 1,6-anhydro-MurNAc termini that mark the ends of PG strands in bacteria, we hypothesized that the incorporation of an anhydromuramyl-containing glycosyl acceptor by TGase into the growing PG may effectively inhibit PG elongation. To explore this possibility, we synthesized 4-O-(N-acetyl-β-d-glucosaminyl)-1,6-anhydro-N-acetyl-β-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, and demonstrated that this anhydromuropeptide and its analogue lacking the peptide, 1-deAA, were both utilized by bacterial TGase as noncanonical anhydro glycosyl acceptors in vitro. The incorporation of an anhydromuramyl moiety into PG strands by TGases afforded efficient termination of glycan chain extension. Moreover, the preliminary in vitro studies of 1-deAA against Staphylococcus aureus showed that 1-deAA served as a reasonable antimicrobial adjunct of vancomycin. These insights imply the potential application of such anhydromuropeptides as novel classes of PG-terminating inhibitors, pointing toward novel strategies in antibacterial agent development. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University National Research Foundation (NRF) Submitted/Accepted version We thank the Ministry of Education (MOE-T2EP30120- 0007), National Research Foundation (CellAg-REQ414940), and A*STAR (A20E5c0087), Singapore to X.-W.L., and National Research Foundation fellowship award (NRF-NRFF12- 2020-0006), and a Nanyang Technological University start-up grant (NTU-SUG) to Y.Q. for financial supports. 2024-03-27T01:23:20Z 2024-03-27T01:23:20Z 2024 Journal Article Zhang, X., Báti, G., Li, C., Guo, A., Yeo, C., Ding, H., Pal, K. B., Xu, Y., Qiao, Y. & Liu, X. (2024). GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation. Journal of the American Chemical Society, 146(11), 7400-7407. https://dx.doi.org/10.1021/jacs.3c12526 0002-7863 https://hdl.handle.net/10356/174229 10.1021/jacs.3c12526 38456799 11 146 7400 7407 en MOE-T2EP30120-0007 CellAg-REQ414940 A20E5c0087 NRF-NRFF12-2020-0006 NTU-SUG Journal of the American Chemical Society © 2024 American Chemical Society. All rights reserved. This article may be downloaded for personal use only. Any other use requires prior permission of the copyright holder. The Version of Record is available online at http://doi.org/10.1021/jacs.3c12526. application/pdf |
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Chemistry Medicine, Health and Life Sciences Anhydromuropeptide Glycosylation Glycosyl acceptor Enzymes Transglycosylase |
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Chemistry Medicine, Health and Life Sciences Anhydromuropeptide Glycosylation Glycosyl acceptor Enzymes Transglycosylase Zhang, Xiao-Lin Báti, Gábor Li, Chenyu Guo, Aoxin Yeo, Claresta Ding, Han Pal, Kumar Bhaskar Xu, Yuan Qiao, Yuan Liu, Xue-Wei GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
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Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assembly. Existing TGase inhibitors like moenomycin and Lipid II analogues always occupy the TGase active sites; other strategies to interfere with proper PG elongation have not been widely exploited. Inspired by the natural 1,6-anhydro-MurNAc termini that mark the ends of PG strands in bacteria, we hypothesized that the incorporation of an anhydromuramyl-containing glycosyl acceptor by TGase into the growing PG may effectively inhibit PG elongation. To explore this possibility, we synthesized 4-O-(N-acetyl-β-d-glucosaminyl)-1,6-anhydro-N-acetyl-β-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, and demonstrated that this anhydromuropeptide and its analogue lacking the peptide, 1-deAA, were both utilized by bacterial TGase as noncanonical anhydro glycosyl acceptors in vitro. The incorporation of an anhydromuramyl moiety into PG strands by TGases afforded efficient termination of glycan chain extension. Moreover, the preliminary in vitro studies of 1-deAA against Staphylococcus aureus showed that 1-deAA served as a reasonable antimicrobial adjunct of vancomycin. These insights imply the potential application of such anhydromuropeptides as novel classes of PG-terminating inhibitors, pointing toward novel strategies in antibacterial agent development. |
author2 |
School of Chemical and Biomedical Engineering |
author_facet |
School of Chemical and Biomedical Engineering Zhang, Xiao-Lin Báti, Gábor Li, Chenyu Guo, Aoxin Yeo, Claresta Ding, Han Pal, Kumar Bhaskar Xu, Yuan Qiao, Yuan Liu, Xue-Wei |
format |
Article |
author |
Zhang, Xiao-Lin Báti, Gábor Li, Chenyu Guo, Aoxin Yeo, Claresta Ding, Han Pal, Kumar Bhaskar Xu, Yuan Qiao, Yuan Liu, Xue-Wei |
author_sort |
Zhang, Xiao-Lin |
title |
GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
title_short |
GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
title_full |
GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
title_fullStr |
GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
title_full_unstemmed |
GlcNAc-1,6-anhydro-MurNAc moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
title_sort |
glcnac-1,6-anhydro-murnac moiety affords unusual glycosyl acceptor that terminates peptidoglycan elongation |
publishDate |
2024 |
url |
https://hdl.handle.net/10356/174229 |
_version_ |
1795302116438310912 |