Genetic Regulation of fermentation organisms : fermentation, regulation, antibiotics

Abstract

An effective fermentation organism is a wasteful creature that overproduces and excretes its metabolic intermediates and end products. Cultures obtained from screening programs usually possess subnormal regulatory controls. Development programs to increase product formation modify the residual control mechanisms so that the culture's "inefficiency" is increased. For production of primary metabolites, feedback inhibition and repression must be bypassed. This is usually accomplished by limiting the intracellular concentration of feedback inhibitors and repressors. Auxotrophic mutants and analogue resistant mutants are most often used for this purpose. Development of fermentations for secondary metabolites, such as antibiotics, is less rational because of our ignorance of the biosynthetic pathways and regulatory controls involved. However, evidence is accumulating that such fermentations are subject to (a) feedback regulation by the idiolite itself, (b)feedback regulation by primary metabolites that share a branched pathway with the secondary metabolite, (c) feedback regulation by inorganic phosphate, (d) catabolite regulation by rapidly utilized carbon sources, (e) induction by primary metabolites, and (f) ATP regulation. Secondary metabolites are not usually formed during growth because the enzymes of secondary metabolism are repressed during the trophophase. We have no clear idea about the type of repression control, but it probably involves growth rate as well as the factors mentioned above. Since the controls discussed above are genetically determined, mutations to increase productivity have been useful to the fermentation industry for over 30 years. Although such strain improvement programs usually involve random screening of survivors of mutagenesis, some recent progress has been made in the application of more rational screening procedures. Mutants are also used to change the spectrum of metabolites, to produce new antibiotics, and to elucidate the pathways of secondary metabolism. Extensive research is now taking place on the genetic mapping of antibiotic-producing microorganisms, especially actinomycetes. The model for this work is the genetic map of Streptomyces coelicolor, and the maps of more recently examined actinomycetes ,including Nocardia, appear to be similar. At least four of the genes of methylenomycin A production in S. coelicolorare plasmid-bound.