The Semi-Synthesis of Labelled Undecaprenol Analogues Allows Rapid Access to Chemical Probes for Antibiotic Targets

Undecaprenol-containing glycolipids (UCGs) are essential biomolecules found in bacteria.1,2 They serve as building blocks for vital bacterial glycopolymers and glyco-proteins, making UCGs and the enzymes that process them excellent antibiotic targets. Although there are many different UCGs, all of them contain the undecaprenol motif, making this an excellent site to incorporate chemical labels, as the resulting labelled undecaprenol analogues could be used to make any UCG desired. However, current strategies to prepare labelled undecaprenol rely on either total synthesis, which is laborious and low-yielding, or chemoenzymatic methods, which are limited by scale and enzyme specificity.3,4 We have developed a new semi-synthetic approach to rapidly prepare labelled undecaprenol analogues from natural undecaprenol that has been extracted from bay leaves. We have elaborated undecaprenol to include several chemical probes such as isotopic labels, fluorophores, spin-labels, and bio-orthogonal tags, yielding a library of new probes for enzymatic testing. All synthetic analogues are processed by undecaprenyl kinase and can be used to prepare labelled UCGs.

References:

[1] H. L. Tytgat, S. Lebeer, Microbiol Mol Biol Rev 2014, 78, 372.
[2] H. Nothaft, C. M. Szymanski, Nat Rev Microbiol 2010, 8, 765.
[3] S. H. Huang, W. S. Wu, L. Y. Huang, W. F. Huang, W. C. Fu, P. T. Chen, J. M. Fang, W. C. Cheng, T. J. Cheng, C. H. Wong, J Am Chem Soc 2013, 135, 17078.
[4] D. K. Lujan, J. A. Stanziale, A. Z. Mostafavi, S. Sharma, J. M. Troutman, Carbohydr Res 2012, 359, 44.