The Impact of Molecular Genetics on Understanding Antibiotic Biosynthesis: Design of New Drugs 

K.J. Linton, Arinthip Thamchaipenet, I.S. Hunter

Institute of Biomedical and Life Sciences, Robertson Laboratory of Biotechnology, University of Glasgow, Glasgow G12 8QQ, U.K.

Article history:
Received June 15, 1994
Accepted September 26, 1994

Summary:
A number of gene clusters for antibiotic production have now been clonal and analysed in considerable detail. Attention has focussed on the genes for β-lactams and for the polyketides, such as erythromycin and oxytetracycline. It is now clear that the polyketides fall into two classes: simple (aromatic) structures are made by complexes of enzymes, each subunit of which has a single enzyme activity, whereas more complex structures (such as the macrolides) are made by very large multi-functional polypeptides. Paradoxically, it is easier to rationalise the biology behind the biosynthesis of the more complex structures. Our understanding of the systems is now at a stage where alteration of the genes has resulted in different compounds being made. Many of the "rules" which determine that a particular structure is made have now been deduced. It is also now possible to engineer strains to make "biological synthons", which can be modified subsequently by chemical means or by further fermentation. This approach will provide a novel route to discovery of new antibiotics. In recent years, it has been realised that many of the metabolites made by microorganisms are useful as therapeutic agents for treating many diseases. The same methodology that is being used for antibiotics can also be applied to them. Molecular genetics is now an integral part of drug-discovery programs, and presents many exciting new prospects.