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Innovative chemical substances from bacteria

Donnerstag, 15. Dezember 2011

Press release No 389 /2011

Synthetic biology finds new ways to manufacture lantibiotics

Roderich Süssmuth and Nediljko Budisa, both professors at the Berlin-based Cluster of Excellence “Unifying Concepts in Catalysis” (UniCat), have developed a new method for the artificial manufacture of lantibiotics. Lantibiotics are a group of antibiotics containing amino acids that do not occur in the proteins of living creatures: non-proteinogenic amino acids. Now, Budisa and Süssmuth’s results have been published in the online edition of the prestigious science journal Angewandte Chemie.

Synthetic amino acids incorporated into peptide-based lantibiotics dramatically increase the chemical diversity of the two-component lantibiotic lichenicidin, which has antibacterial properties. This procedure enables the biotechnological manufacture of a variety of different lichenicidin compounds, paving the way towards new antibiotics that can be exploited in human medicine.

Süssmuth and Budisa aim to broaden traditional, natural cellular chemistry with the introduction of a new method for the synthesis of bacterial lantibiotics. In nature, lantibiotics are first ribosomally synthesized in their pre-propeptide form using 20 standard amino acids, and then converted into biologically active lantibiotics using enzymes. In their new study, Süssmuth and Budisa show that the incorporation of non-naturally occurring amino acids greatly increases the synthetic scope. “It is as though we have a box full of Lego bricks to which we are adding more bricks with new linking options," says Budisa. "These enable us to synthesize substances that normal living cells cannot manufacture, such as lantibiotics with chemical properties that would not occur through natural evolution.”

Süssmuth and his colleague are the first to produce the lantibiotic lichenicidin using genetically modified Escherichia coli bacteria, a feat they accomplished recently. This consists of two peptides that were modified after their incorporation and that, in combination with each other, have an antimicrobial effect.  The bacterial host Escherichia coli is, to date, the most efficient platform for genetic engineering work and it enables the incorporation of one or more synthetic amino acids into peptide-based antibiotics. It is therefore possible to use classic genetic engineering technology for the production of synthetic antibiotics.

“The research carried out by Budisa and Süssmuth shows how a whole-cell catalyst could work. This presupposes the coupling of many enzymatic processes, which is part of the core activity of the UniCat network,” says Prof. Matthias Driess, chairman of the Cluster of Excellence.

There are exactly 20 natural amino acids. These are the building blocks for the manufacture of proteins by living beings. Budisa and his co-researcher have developed a process through which almost every one of the 20 natural amino acids can be replaced with synthetic alternatives, breaking the boundaries of traditional genetic engineering. They call this new biochemical process "codon emancipation".

Lantibiotics and their medicinal significance

Lantibiotics are ribosomally synthesized peptide antibiotics that are generated by an enzymatic cascade. In nature, lantibiotics must first pass the pre-propeptide state with 20 canonical amino acids as standard building blocks before they are effectively transformed into bioactive lantibiotics using posttranslational modification by a battery of enzymes that selectively process various types of amino acid side chains.

The lantibiotic nisin has been used for over 40 years throughout the world as an organic food preservative, with no emergence of bacterial resistance, while in contrast commercially available antibiotics have become increasingly limited in usefulness due to the appearance of multi-resistant bacteria strains in recent decades. This means that lantibiotics are valuable anti-microbial agents with great potential for medicinal uses in humans.

The biotechnological manufacture of these valuable substances is extremely interesting, particularly given that the re-engineering of the structures of naturally occurring lantibiotics means that their pharmaceutical characteristics can be further improved.

The genetic code and the concept of codon emancipation

The genetic code was solved in 1966 and is identical for all living creatures. This means that in every organism, a specific sequence of nucleic acids in the DNA carries the same protein molecule.

The genetic code determines the way in which the sequence of bases adenine (A), cytosine (C), guanine (G) and thymine (T) are translated into protein. Every three bases stand for one amino acid, in a triplet known as a codon. There are only 64 codons that generate 20 amino acids. This means that the majority of amino acids are encoded by several codons.

For example, the amino acid arginine can be represented using the six codons CGG, CGA, CGC, CGU, AGG and AGA. AGG and AGA are used very seldom in bacteria such as Escherichia coli. Thus theoretically, for example, all AGGs in the genetic makeup of a living creature could be allocated a new, non-natural amino acid. The cell is then said to be codon emancipated, meaning that the old chemistry has been replaced with new.

UniCat

“Unifying Concepts in Catalysis” (UniCat) is the sole Cluster of Excellence researching the economically important field of catalysis. More than 250 chemists, physicists, biologists and engineers from four universities and two Max Planck research institutes from Berlin and Potsdam are involved in this interdisciplinary research network. The Cluster is hosted by the Technische Universität Berlin. UniCat receives funding of approximately € 5.6 million each year as part of the Excellence Initiative of the German Research Foundation.

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References:

Roderich Süssmuth, Florian Oldach, Rashed Al Toma, Anja Kuthning, Tânia Caetano, Sónia Mendo, Nediljko Budisa,
Congeneric Lantibiotics from Ribosomal In Vivo Peptide Synthesis with Noncanonical Amino Acids
Angewandte Chemie. Int. Ed., 2011, 50, Article first published online: 30 NOV 2011

http://dx.doi.org/10.1002/anie.201106154

For further information please contact:

Prof. Dr. Roderich Süssmuth
TU Berlin
Department of Chemistry
Tel.: 030/314-78774

www.biochemie.tu-berlin.de
Prof. Dr. Nediljko Budisa
TU Berlin
Department of Chemistry
Tel.: 030/314-23661

www.biocat.tu-berlin.de
Dr. Martin Penno
UniCat Cluster of Excellence
Public Relations Officer
TU Berlin
Tel.: 030/314-28592

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