Peptidoglycan Glycosyltransferase Substrate Mimics As Templates for the Design of New Antibacterial Drugs

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2013 Apr 2

PMID 23543824

Citations 19

Authors

Adeline Derouaux

Eric Sauvage

Mohammed Terrak

Affiliations

Soon will be listed here.

Abstract

Peptidoglycan (PG) is an essential net-like macromolecule that surrounds bacteria, gives them their shape, and protects them against their own high osmotic pressure. PG synthesis inhibition leads to bacterial cell lysis, making it an important target for many antibiotics. The final two reactions in PG synthesis are performed by penicillin-binding proteins (PBPs). Their glycosyltransferase (GT) activity uses the lipid II precursor to synthesize glycan chains and their transpeptidase (TP) activity catalyzes the cross-linking of two glycan chains via the peptide side chains. Inhibition of either of these two reactions leads to bacterial cell death. β-lactam antibiotics target the transpeptidation reaction while antibiotic therapy based on inhibition of the GTs remains to be developed. Ongoing research is trying to fill this gap by studying the interactions of GTs with inhibitors and substrate mimics and utilizing the latter as templates for the design of new antibiotics. In this review we present an updated overview on the GTs and describe the structure-activity relationship of recently developed synthetic ligands.

Citing Articles

Dual targeting of the class V lanthipeptide antibiotic cacaoidin.

Deisinger J, Arts M, Kotsogianni I, Puls J, Grein F, Ortiz-Lopez F iScience. 2023; 26(4):106394.

PMID: 37013189 PMC: 10066520. DOI: 10.1016/j.isci.2023.106394.

Peptidoglycan pathways: there are still more!.

Helal A, Sayed A, Omara M, Elsebaei M, Mayhoub A RSC Adv. 2022; 9(48):28171-28185.

PMID: 35530449 PMC: 9071014. DOI: 10.1039/c9ra04518j.

Rational structural modification of the isatin scaffold to develop new and potent antimicrobial agents targeting bacterial peptidoglycan glycosyltransferase.

Wang Y, Liang Z, Zheng Y, Leung A, Yan S, So P RSC Adv. 2022; 11(29):18122-18130.

PMID: 35480164 PMC: 9033243. DOI: 10.1039/d1ra02119b.

The Bacterial Cell Wall: From Lipid II Flipping to Polymerization.

Kumar S, Mollo A, Kahne D, Ruiz N Chem Rev. 2022; 122(9):8884-8910.

PMID: 35274942 PMC: 9098691. DOI: 10.1021/acs.chemrev.1c00773.

Recent advances in enzymatic synthesis of β-glucan and cellulose.

Bulmer G, de Andrade P, Field R, van Munster J Carbohydr Res. 2021; 508:108411.

PMID: 34392134 PMC: 8425183. DOI: 10.1016/j.carres.2021.108411.

References

Yuan Y, Barrett D, Zhang Y, Kahne D, Sliz P, Walker S . Crystal structure of a peptidoglycan glycosyltransferase suggests a model for processive glycan chain synthesis. Proc Natl Acad Sci U S A. 2007; 104(13):5348-53. PMC: 1817829. DOI: 10.1073/pnas.0701160104. View

Taylor J, Li X, Oberthur M, Zhu W, Kahne D . The total synthesis of moenomycin A. J Am Chem Soc. 2006; 128(47):15084-5. PMC: 2553521. DOI: 10.1021/ja065907x. View

Garneau S, Qiao L, Chen L, Walker S, Vederas J . Synthesis of mono- and disaccharide analogs of moenomycin and lipid II for inhibition of transglycosylase activity of penicillin-binding protein 1b. Bioorg Med Chem. 2004; 12(24):6473-94. DOI: 10.1016/j.bmc.2004.09.019. View

Huang C, Shih H, Lin L, Tien Y, Cheng T, Cheng W . Crystal structure of Staphylococcus aureus transglycosylase in complex with a lipid II analog and elucidation of peptidoglycan synthesis mechanism. Proc Natl Acad Sci U S A. 2012; 109(17):6496-501. PMC: 3340074. DOI: 10.1073/pnas.1203900109. View

Fraipont C, Sapunaric F, Zervosen A, Auger G, Devreese B, Lioux T . Glycosyl transferase activity of the Escherichia coli penicillin-binding protein 1b: specificity profile for the substrate. Biochemistry. 2006; 45(12):4007-13. DOI: 10.1021/bi051055m. View

Cheng T, Sung M, Liao H, Chang Y, Chen C, Huang C . Domain requirement of moenomycin binding to bifunctional transglycosylases and development of high-throughput discovery of antibiotics. Proc Natl Acad Sci U S A. 2008; 105(2):431-6. PMC: 2206553. DOI: 10.1073/pnas.0710868105. View

Gampe C, Tsukamoto H, Wang T, Walker S, Kahne D . Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics. Tetrahedron. 2012; 67(51):9771-9778. PMC: 3322638. DOI: 10.1016/j.tet.2011.09.114. View

Dumbre S, Derouaux A, Lescrinier E, Piette A, Joris B, Terrak M . Synthesis of modified peptidoglycan precursor analogues for the inhibition of glycosyltransferase. J Am Chem Soc. 2012; 134(22):9343-51. DOI: 10.1021/ja302099u. View

Breukink E, van Heusden H, Vollmerhaus P, Swiezewska E, Brunner L, Walker S . Lipid II is an intrinsic component of the pore induced by nisin in bacterial membranes. J Biol Chem. 2003; 278(22):19898-903. DOI: 10.1074/jbc.M301463200. View

10.

Mohammadi T, van Dam V, Sijbrandi R, Vernet T, Zapun A, Bouhss A . Identification of FtsW as a transporter of lipid-linked cell wall precursors across the membrane. EMBO J. 2011; 30(8):1425-32. PMC: 3102273. DOI: 10.1038/emboj.2011.61. View

11.

Derouaux A, Turk S, Olrichs N, Gobec S, Breukink E, Amoroso A . Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor. Biochem Pharmacol. 2011; 81(9):1098-105. DOI: 10.1016/j.bcp.2011.02.008. View

12.

Sung M, Lai Y, Huang C, Chou L, Shih H, Cheng W . Crystal structure of the membrane-bound bifunctional transglycosylase PBP1b from Escherichia coli. Proc Natl Acad Sci U S A. 2009; 106(22):8824-9. PMC: 2689995. DOI: 10.1073/pnas.0904030106. View

13.

VanNieuwenhze M, Mauldin S, Aikins J, Blaszczak L . The total synthesis of lipid I. J Am Chem Soc. 2001; 123(29):6983-8. DOI: 10.1021/ja016082o. View

14.

Terrak M, Ghosh T, van Heijenoort J, Van Beeumen J, Lampilas M, Aszodi J . The catalytic, glycosyl transferase and acyl transferase modules of the cell wall peptidoglycan-polymerizing penicillin-binding protein 1b of Escherichia coli. Mol Microbiol. 1999; 34(2):350-64. DOI: 10.1046/j.1365-2958.1999.01612.x. View

15.

Heaslet H, Shaw B, Mistry A, Miller A . Characterization of the active site of S. aureus monofunctional glycosyltransferase (Mtg) by site-directed mutation and structural analysis of the protein complexed with moenomycin. J Struct Biol. 2009; 167(2):129-35. DOI: 10.1016/j.jsb.2009.04.010. View

16.

Wang T, Lupoli T, Sumida Y, Tsukamoto H, Wu Y, Rebets Y . Primer preactivation of peptidoglycan polymerases. J Am Chem Soc. 2011; 133(22):8528-30. PMC: 3119865. DOI: 10.1021/ja2028712. View

17.

Zhang Y, Fechter E, Wang T, Barrett D, Walker S, Kahne D . Synthesis of heptaprenyl-lipid IV to analyze peptidoglycan glycosyltransferases. J Am Chem Soc. 2007; 129(11):3080-1. PMC: 3222299. DOI: 10.1021/ja069060g. View

18.

Barreteau H, Kovac A, Boniface A, Sova M, Gobec S, Blanot D . Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008; 32(2):168-207. DOI: 10.1111/j.1574-6976.2008.00104.x. View

19.

Lovering A, de Castro L, Lim D, Strynadka N . Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis. Science. 2007; 315(5817):1402-5. DOI: 10.1126/science.1136611. View

20.

Schwartz B, Markwalder J, Wang Y . Lipid II: total synthesis of the bacterial cell wall precursor and utilization as a substrate for glycosyltransfer and transpeptidation by penicillin binding protein (PBP) 1b of Escherichia coli. J Am Chem Soc. 2001; 123(47):11638-43. DOI: 10.1021/ja0166848. View