7-1.3.1 Traditional Method of Strain Improvement

• The remarkable increases in antibiotic productivity and the resulting decreases in costs have resulted due to mutation and screening for higher producing microbial strains. In recent years, efforts have been devoted to miniaturize and automate the screening procedures and to enhance the frequency of improved strains by selection procedures, e.g., the isolation of anti-metabolite-resistant mutants in cases where the natural metabolite is a precursor, an inhibitor or a co-repressor of a biosynthetic pathway.
  
  
• Mutation has also served to shift the proportion of metabolites production in a fermentation broth to a more favorable distribution, to elucidate the pathways of secondary metabolism, and to yield new antibiotics.
  
  
• Targeted mutagenesis: It involves introduction of mutations at a specific location in DNA. As many antibiotics, growth hormones, regulatory factors production genes have now been cloned, targeted mutagenesis of the cloned DNA can be performed in vitro, followed by transformation of the recipient organism.
  
  
• The major problems of the classic strain improvement procedure based on random mutagenesis were the very low probability of introducing mutations into relevant genes and high rate of unwanted mutations in other, unrelated genes.

7-1.3.2 Classical Genetics

The most effective use of classical genetics in the past was the backcrossing of overproducing strains with parent strains to improve the vigor of mutant strains.

• After backcrossing such a strain with the wild type, progeny cells are produced that have inherited the overproducing traits from the mutant parent and the wild-type hardiness and vigor from the wild-type parent.
  
  
• Priorly this was not possible with Penicillium, which lacks a true sexual cycle. However, a parasexual cycle resulting in the production of heterokaryons was discovered in Penicillium in 1958 and was used to improve the strains.
  
  
• Protoplast fusion is relatively a new versatile technique to induce or promote genetic recombination in a variety of prokaryotic and eukaryotic cell especially, industrially useful microorganisms such as Streptomycete ambofaciens, Micromonsporae chinospora, because it breaks the barriers to genetic exchange. Another use of protoplast fusion has been the recombination of different strains from the same or different species to yield new antibiotics such as anthracyclines, aminoglycosides and rifamycins. Protoplast fusion has also been useful in elimination of an undesirable component from penicillin broths imposed by conventional mating systems.