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The elucidation and manipulation of the biosynthesis of aminoglycoside antibiotics

Objective



Research objectives and content
The emergence of methicillin resistant Staphylococcus aureus (MRSA) and the rise in the number of tuberculosis cases in the Western World, highlights the unrelenting increase in the number of bacterial strains resistant to known antibiotics. No new class of clinically useful antibiotics have been discovered in the last decade, therefore, to combat resistant strains modification of existing antibiotics must be vigorously explored. To achieve this it is proposed to use gene shuffling techniques to alter the producing strains biosynthetic machinery to make novel antibiotics.
Aminoglycosides are a large class of clinically important antibiotics that includes such significant compounds as neomycin and gentamicin. The project will involve the cloning of some of the biosynthetic genes for butirosin; an aminoglycoside produced by Bacillus circulans . Butirosin has a unique amino acid bonded to it's deoxystreptamine ring that has be shown to prevent deactivation of this antibiotic by many of the enzymes that confer resistance against other aminoglycosides. It is proposed to exploit this observation by transfering the genes that are responsible for adding 2-hydroxy4-amino-butyric acid to Streptomyces strains that produce neomycin and gentamicin. This should produce novel aminoglycosides that will hopefully be active against the growing number of MRSA stains. Training content (objective, benefit and expected impact)
The project will provide training in molecular biology, mechanistic enzymology and chemical synthesis. The impact of the work is potentially of great significance because of the problems of antibiotic resistance. Links with industry / industrial relevance (22)
It is anticipated that any novel Aminoglycoside Antibiotic found by this research will be developed by major Phannaceutic companies

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

University of Cambridge
Address
Lensfield Road
CB2 1EW Cambridge
United Kingdom

Participants (1)

Not available
Italy