[Filamentous fungi as cellular factories: Biodiversity of secondary metabolites]

The increase in the production of beta-lactam antibiotics has been carried out traditionally by classical mutagenic techniques, this method has been shown to be very effective and it has been the responsible for high increases in production. The development of DNA recombinant techniques in filamentous fungi has allowed the direct use of the genes involved in b-lactam biosynthesis. First the increase in the gene copy number of some particular genes has allowed slight increases of beta-lactam antibiotics production, thought in only some cases. In addition, the exchange of the promoter region of some genes with low level of transcription (e.g. the promoter region of the cefG gene of A. chrysogenum) has given rise to higher increases. Finally the modification of the flux of the beta-lactam antibiotics biosynthesis precursors (e.g. Increase of the alpha-aminoadipic acid pool) has yielded the highest increase in the penicillin production. Thus the genetic manipulation of the filamentous fungi has resulted in improvements in the production, though until now they have not exceeded the increases achieved by classical mutation. When one limiting step is improved, other new, limitations of the production appear to prevent important increases in the beta-lactam production.