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Elucidation and manipulation of the aminoglycoside antibiotic butirosin


Research objectives and content
Due to the increasing number of antibiotic resistances in the western world it is necessary to discover novel antibiotics.
One example is butirosin. Its special feature is the 2-hydroxyl-4-amino butyric acid side chain which acts as a protecting group against the attack of the enzyme aminoglycosid phosphotransferase produced by resistant bacteria.
Also kanamycin has been syntheticlly altered in this way giving amikacin which one of the widely used antibiotic.
Our idea first is to introduce this protecting chain into other already known antibiotics with clinical importance, such as gentamycin, etc. Secondly the generation of amikacin enzymatically within the kanamycin-producing bacteria would overgo the purification of kanamycin and the following modification. One can isolate the desired amikacin straight away. Here, of course, we see strong links between university and industry. This part is currently in progress by making a cosmid library. The library will then be screened using different probes in order to obtain the desired genes.
A second task of this work will be the elucidation of the key steps of the formation of butirosin. Therefore the enzymes 2-deoxy-scyllo-inosose synthase and 2-deoxy-ssyllo-inosose aminase will be necessary to locate on the genom and then to overexpress them in order to carry out kinetic studies. This will tell us the reaction mechanism of these higly interesting reactions.
Furthermore the gene for the 2-deoxy-scyllo-inosose synthase seems to have similarities with the dehydroquinate synthase an enzvme from the shikimate pathway.


University of Cambridge
Lensfield Road
CB2 1EW Cambridge
United Kingdom

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