Helmholtz Institute develops a new path to more effective antibiotics

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Resistance to antibiotics has increased alarmingly in recent years. For example, in France the resistance of pneumococci has risen to 58% due to high rates of antibiotic prescription. Medical experts are sounding the alarm. Pharmacologists are seeking new antibiotically effective substances.

A technique has been developed at the Helmholtz Institute for Biomedical Research at the RWTH Aachen University which allows antibiotic substances to be produced with high purity levels and at low cost.

“Our work is based on sugar molecules, which are the essential components of many antibiotics,” says Professor Lothar Elling of the eight years that have now gone into the work. Under two EU projects, he and his PhD students modified the sugar structures of antibiotics in order to gain as broad a possible a spectrum of efficacy. “Through combination of the modified molecules we are able to obtain multiple variance possibilities, which we are currently testing for their effectiveness.”

The technique of combinatorial biocatalysis developed by the Helmholtz Institute with partners in Cambridge, Freiburg, Hanover and Wuppertal, consists of three enzyme modules. The enzyme technologists create the first sugar molecule, which serves as the precursor for further sugar molecules, on the basis of saccherose - standard household sugar - with the help of sucrose synthase (SuSy). In the next step this precursor is converted by means of a multitude of enzymatic steps into a complex sugar molecule. “Thus,” as Professor Elling explains, “very complicated sugar molecules are produced from the renewable raw material saccharose, which are integrated into antibiotic precursors as the active constituent.” This takes place in the third phase through enzymatic transfer of the sugar molecules onto the skeletal structure of an antibiotic structure. At the same time the employed glycosyltransferases create as a by-product a substance which can be re-integrated into the first step. “In this way,” continues Prof. Elling, “we get a closed system for the production of complex sugar molecules and spare ourselves the need for extensive and costly isolation.” Unlike the usual alternative technique of combinatorial biosynthesis, this method enables the creation of pure molecular structures which can be produced inexpensively in large quantities.

The technique is currently undergoing further development at the Helmholtz Institute with enzyme columns which are to reach bench-scale syntheses on the scale of up to 500 mg. “That’s enough for us to conduct the necessary tests,” says Elling. Four substances have already been tested. They are all antibiotically active, but only as effective as their basic structure. “In order to develop substances with greater efficacy, we have to systematically run through the different possibilities,” said Prof. Elling about the next challenges. “An industry partner would be very welcome to help shape the further development.” However, he estimates that it will still take a good five years for life-saving drugs to emerge from the enzymatic columns technique. That is the usual period of time between development and commercial production of an antibiotic.

Toni Wimmer of http://www.rwth-aachen.de/

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