Glycopeptide antibiotics:

Bioengineering for novel derivatives and improved production yields

Glycopeptides, such as vancomycin and teicoplanin, are drugs of last resort for clinical treatment of antibiotic resistant Gram-positive bacteria, including methicillin resistant Staphylococcus aureus (MRSA). However, also to glycopeptide antibiotics resistance has emerged. In addition, side effects (such as nephrotoxicity) limit the application of these highly effective drugs. Therefore, novel glycopeptide derivatives are required.

Since the molecular structure of glycopeptides is highly complex, the development of active derivatives is limited by chemical approaches. In order to modify the compounds by genetic engineering and synthetic biology approaches, the biosynthesis of glycopeptides was elucidated in detail. Now, we understand biochemistry and genetics of almost all biosynthetic steps. This knowledge is applied to construct optimized glycopeptides, to increase production yield, and to identify novel glycopeptide producing bacteria by genome mining.

Selected publications on glycopeptides:

Wohlleben, W., Y. Mast, E. Stegmann, N. Ziemert. 2016. Antibiotic Drug Discovery. Microbial Biotechnology 9:541-548 doi:10.1111/1751-7915.12388.

Spohn, M., N. Kirchner, A. Kulik, A. Jochim, F. Wolf, P. Muenzer, O. Borst, H. Gross, W. Wohlleben, E. Stegmann. 2014. Overproduction of ristomycin A by activation of a silent gene cluster in Amycolatopsis japonicum MG417-CF17. Antimicrobial Agents & Chemotherapy 58:6185-96 doi:10.1128/AAC.03512-14.

Wohlleben, W., Y. Mast, G. Muth, M. Röttgen, E. Stegmann, T. Weber. 2012. Synthetic Biology of Secondary Metabolite Biosynthesis in Actinomycetes: Engineering precursor supply as a way to optimize antibiotic production. FEBS Letters 586:2171-2176 doi:10.1016/j.febslet.2012.04.025.

Stegmann, E., H.-J. Frasch, W. Wohlleben. 2010. Glycopeptide biosynthesis in the context of basic cellular functions. Current Opinion in Microbiology 5:595-602 doi:10.1016/j.mib.2010.08.011.

Thykaer, J., J. Nielsen, W. Wohlleben, T. Weber, M. Gutknecht, A.E. Lantz, E. Stegmann. 2010. Increased glycopeptide production after overexpression of shikimate pathway genes being part of the balhimycin biosynthetic gene cluster. Metabolism Eng. 12:455-461 doi:10.1016/j.ymben.2010.05.001.

Wohlleben, W., E. Stegmann, R.D. Süssmuth. 2009. Molecular genetic approaches to analyze glycopeptide biosynthesis. Methods Enzymology 458:459-486 doi:10.1016/S0076-6879(09)04818-6.

Bischoff, D., S. Pelzer, B. Bister, G.J. Nicholson, S. Stockert, M. Schirle, W. Wohlleben, G. Jung, R.D. Süssmuth. 2001. The bosynthesis of vancomycin-type glycopeptide antibiotics-The order of the cyclization steps. Angewandte Chemie Int. Ed. Engl. 40:4688-4691 doi:10.1002/1521-3773(20011217).

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