Peptidoglycan glycosyltransferase substrate mimics as templates for the design of new antibacterial drugs.

[en] 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. beta-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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Derouaux, Adeline ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Sauvage, Eric ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Terrak, Mohammed ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Language :

English

Title :

Peptidoglycan glycosyltransferase substrate mimics as templates for the design of new antibacterial drugs.

Publication date :

2013

Journal title :

Frontiers in Immunology

eISSN :

1664-3224

Publisher :

Frontiers Research Foundation, Lausanne, Switzerland

Volume :

Pages :

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

http://www.ncbi.nlm.nih.gov/pubmed/23543824

Available on ORBi :

since 15 April 2013

Statistics

Number of views

75 (5 by ULiège)

Number of downloads

155 (1 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Adachi, M., Zhang, Y., Leimkuhler, C., Sun, B., Latour, J. V., and Kahne, D. E. (2006). Degradation and reconstruction of moenomycin A and derivatives: dissecting the function of the isoprenoid chain. J. Am. Chem. Soc. 128, 14012-14013.
Baizman, E. R., Branstrom, A. A., Longley, C. B., Allanson, N., Sofia, M. J., Gange, D., et al. (2000). Antibacterial activity of synthetic analogues based on the disaccharide structure of moenomycin, an inhibitor of bacterial transglycosylase. Microbiology 146(Pt 12), 3129-3140.
Barreteau, H., Kovac, A., Boniface, A., Sova, M., Gobec, S., and Blanot, D. (2008). Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol. Rev. 32, 168-207.
Breukink, E., Van Heusden, H. E., Vollmerhaus, P. J., Swiezewska, E., Brunner, L., Walker, S., et al. (2003). Lipid II is an intrinsic component of the pore induced by nisin in bacterial membranes. J. Biol. Chem. 278, 19898-19903.
Butaye, P., Devriese, L. A., and Haesebrouck, F. (2003). Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria. Clin. Microbiol. Rev. 16, 175-188.
Cheng, T. J., Sung, M. T., Liao, H. Y., Chang, Y. F., Chen, C. W., Huang, C. Y., et al. (2008). Domain requirement of moenomycin binding to bifunctional transglycosylases and development of high-throughput discovery of antibiotics. Proc. Natl. Acad. Sci. U.S.A. 105, 431-436.
den Blaauwen, T., De Pedro, M. A., Nguyen-Distèche, M., and Ayala, J. A. (2008). Morphogenesis of rod-shaped sacculi. FEMS Microbiol. Rev. 32, 321-344.
Derouaux, A., Turk, S., Olrichs, N. K., Gobec, S., Breukink, E., Amoroso, A., et al. (2011). Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor. Biochem. Pharmacol. 81, 1098-1105.
Dumbre, S., Derouaux, A., Lescrinier, E., Piette, A., Joris, B., Terrak, M., et al. (2012). Synthesis of modified peptidoglycan precursor analogues for the inhibition of glycosyltransferase. J. Am. Chem. Soc. 134, 9343-9351.
Fraipont, C., Sapunaric, F., Zervosen, A., Auger, G., Devreese, B., Lioux, T., et al. (2006). Glycosyl transferase activity of the Escherichia coli penicillin-binding protein 1b: specificity profile for the substrate. Biochemistry 45, 4007-4013.
Gampe, C. M., Tsukamoto, H., Wang, T. S., Walker, S., and Kahne, D. (2011). Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics. Tetrahedron 67, 9771-9778.
Garneau, S., Qiao, L., Chen, L., Walker, S., and Vederas, J. C. (2004). Synthesis of mono and disaccharide analogs of moenomycin and lipid II for inhibition of transglycosylase activity of penicillin-binding protein 1b. Bioorg. Med. Chem. 12, 6473-6494.
Goldman, R. C., and Gange, D. (2000). Inhibition of transglycosylation involved in bacterial peptidoglycan synthesis. Curr. Med. Chem. 7, 801-820.
Halliday, J., Mckeveney, D., Muldoon, C., Rajaratnam, P., and Meutermans, W. (2006). Targeting the forgotten transglycosylases. Biochem. Pharmacol. 71, 957-967.
Heaslet, H., Shaw, B., Mistry, A., and Miller, A. A. (2009). 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. 167, 129-135.
Hecker, S. J., Minich, M. L., and Lackey, K. (1990). Synthesis of compounds designed to inhibit bacterial cell wall transglycosylation. J. Org. Chem. 55, 4904-4911.
Helassa, N., Vollmer, W., Breukink, E., Vernet, T., and Zapun, A. (2012). The membrane anchor of penicillin-binding protein PBP2a from Streptococcus pneumoniae influences peptidoglycan chain length. FEBS J. 279, 2071-2081.
Huang, C. Y., Shih, H. W., Lin, L. Y., Tien, Y. W., Cheng, T. J., Cheng, W. C., et al. (2012). 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. 109, 6496-6501.
Lovering, A. L., De Castro, L., and Strynadka, N. C. (2008). Identification of dynamic structural motifs involved in peptidoglycan glycosyltransfer. J. Mol. Biol. 383, 167-177.
Lovering, A. L., De Castro, L. H., Lim, D., and Strynadka, N. C. (2007). Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis. Science 315, 1402-1405.
McPherson, D. C., and Popham, D. L. (2003). Peptidoglycan synthesis in the absence of class A penicillin-binding proteins in Bacillus subtilis. J. Bacteriol. 185, 1423-1431.
Mohammadi, T., Van Dam, V., Sijbrandi, R., Vernet, T., Zapun, A., Bouhss, A., et al. (2011). Identification of FtsW as a transporter of lipid-linked cell wall precursors across the membrane. EMBO J. 30, 1425-1432.
Offant, J., Terrak, M., Derouaux, A., Breukink, E., Nguyen-Disteche, M., Zapun, A., et al. (2010). Optimization of conditions for the glycosyltransferase activity of penicillin-binding protein 1a from Thermotoga maritima. FEBS J. 277, 4290-4298.
Ostash, B., Saghatelian, A., and Walker, S. (2007). A streamlined metabolic pathway for the biosynthesis of moenomycin A. Chem. Biol. 14, 257-267.
Perlstein, D. L., Zhang, Y., Wang, T. S., Kahne, D. E., and Walker, S. (2007). The direction of glycan chain elongation by peptidoglycan glycosyltransferases. J. Am. Chem. Soc. 129, 12674-12675.
Qiao, L., and Vederas, J. C. (1993). Synthesis of a C-phosphonate disaccharide as a potential inhibitor of peptidoglycan polymerization by transglycosylase. J. Org. Chem. 58, 3480-3482.
Sauvage, E., Kerff, F., Terrak, M., Ayala, J. A., and Charlier, P. (2008). The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol. Rev. 32, 234-258.
Schwartz, B., Markwalder, J. A., Seitz, S. P., Wang, Y., and Stein, R. L. (2002). A kinetic characterization of the glycosyltransferase activity of Escherichia coli PBP1b and development of a continuous fluorescence assay. Biochemistry 41, 12552-12561.
Schwartz, B., Markwalder, J. A., and Wang, Y. (2001). 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. 123, 11638-11643.
Shih, H. W., Chang, Y. F., Li, W. J., Meng, F. C., Huang, C. Y., Ma, C., et al. (2012). Effect of the peptide moiety of lipid II on bacterial transglycosylase. Angew. Chem. Int. Ed. Engl. 51, 10123-10126.
Shih, H. W., Chen, K. T., Chen, S. K., Huang, C. Y., Cheng, T. J., Ma, C., et al. (2010). Combinatorial approach toward synthesis of small molecule libraries as bacterial transglycosylase inhibitors. Org. Biomol. Chem. 8, 2586-2593.
Shih, H. W., Chen, K. T., Cheng, T. J., Wong, C. H., and Cheng, W. C. (2011). A new synthetic approach toward bacterial transglycosylase substrates, Lipid II and Lipid IV. Org. Lett. 13, 4600-4603.
Sofia, M. J., Allanson, N., Hatzenbuhler, N. T., Jain, R., Kakarla, R., Kogan, N., et al. (1999). Discovery of novel disaccharide antibacterial agents using a combinatorial library approach. J. Med. Chem. 42, 3193-3198.
Sung, M. T., Lai, Y. T., Huang, C. Y., Chou, L. Y., Shih, H. W., Cheng, W. C., et al. (2009). Crystal structure of the membrane-bound bifunctional transglycosylase PBP1b from Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 106, 8824-8829.
Taylor, J. G., Li, X., Oberthur, M., Zhu, W., and Kahne, D. E. (2006). The total synthesis of moenomycin A. J. Am. Chem. Soc. 128, 15084-15085.
Terrak, M., Ghosh, T. K., Van Heijenoort, J., Van Beeumen, J., Lampilas, M., Aszodi, J., et al. (1999). The catalytic, glycosyl transferase and acyl transferase modules of the cell wall peptidoglycan-polymerizing penicillin-binding protein 1b of Escherichia coli. Mol. Microbiol. 34, 350-364.
Terrak, M., Sauvage, E., Derouaux, A., Dehareng, D., Bouhss, A., Breukink, E., et al. (2008). Importance of the conserved residues in the peptidoglycan glycosyltransferase module of the class A penicillin-binding protein 1b of Escherichia coli. J. Biol. Chem. 283, 28464-28470.
VanNieuwenhze, M. S., Mauldin, S. C., Zia-Ebrahimi, M., Aikins, J. A., and Blaszczak, L. C. (2001). The total synthesis of lipid I. J. Am. Chem. Soc. 123, 6983-6988.
VanNieuwenhze, M. S., Mauldin, S. C., Zia-Ebrahimi, M., Winger, B. E., Hornback, W. J., Saha, S. L., et al. (2002). The first total synthesis of lipid II: the final monomeric intermediate in bacterial cell wall biosynthesis. J. Am. Chem. Soc. 124, 3656-3660.
Vollmer, W., Blanot, D., and De Pedro, M. A. (2008). Peptidoglycan structure and architecture. FEMS Microbiol. Rev. 32, 149-167.
Wang, T. S., Lupoli, T. J., Sumida, Y., Tsukamoto, H., Wu, Y., Rebets, Y., et al. (2011). Primer preactivation of peptidoglycan polymerases. J. Am. Chem. Soc. 133, 8528-8530.
Welzel, P. (2005). Syntheses around the transglycosylation step in peptidoglycan biosynthesis. Chem. Rev. 105, 4610-4660.
Ye, X. Y., Lo, M. C., Brunner, L., Walker, D., Kahne, D., and Walker, S. (2001). Better substrates for bacterial transglycosylases. J. Am. Chem. Soc. 123, 3155-3156.
Yuan, Y., Barrett, D., Zhang, Y., Kahne, D., Sliz, P., and Walker, S. (2007). Crystal structure of a peptidoglycan glycosyltransferase suggests a model for processive glycan chain synthesis. Proc. Natl. Acad. Sci. U.S.A. 104, 5348-5353.
Yuan, Y., Fuse, S., Ostash, B., Sliz, P., Kahne, D., and Walker, S. (2008). Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design. ACS Chem. Biol. 3, 429-436.
Zhang, Y., Fechter, E. J., Wang, T. S., Barrett, D., Walker, S., and Kahne, D. E. (2007). Synthesis of heptaprenyl-lipid IV to analyze peptidoglycan glycosyltransferases. J. Am. Chem. Soc. 129, 3080-3081.