Fed-Batch Bioproduction of Spectinomycin
7
as the nitrogen source. When the defined media contained both ammonium salts
and proline, the microorganism preferentially utilized the ammonium salts for
growth and proline for novobiocin production. Clearly, a nitrogen regulatory
phenomena controlled the antibiotic production. Similarly, production of
gramicidin S by Bacillus brevis specifically required phenylanaline. In another
report, highest yields of cephalosporin by Streptomyces clavuligerus [6] required
supplementation of medium with certain amino acids and urea.
These examples illustrate two possible circumstances of nitrogen incorporation - (i) including a direct precursor into the antibiotic molecule and (ii)
utilizing the nitrogen atom or a nitrogen group by an antibiotic-specific reaction
on a specific intermediate. In the first case, supplying the production medium
with the direct precursor or a source from which the molecule is easily available
significantly enhances the yield. In the second case, optimizing the medium with
several suitable sources of nitrogen is necessary.
Several routes of nitrogen regulatory phenomena include:
a) Control at the catabolic level.
b) Regulation at the biosynthetic level.
c) Transport of metabolites.
d) Modulation of intracellular concentration of free metabolites.
e) Protein turnover and degradation.
f) Regulation of antibiotic-synthetase formation.
All regulatory mechanisms are manifestations of expression at the genetic
level. Expression of the antibiotic genes depend on many factors, both external
and internal. Nitrogen is just one of the many external factors influencing
these mechanisms. Antibiotic biosynthesis control occurs at the transcription, the
translational and as well as the post translational levels. Regulatory signals from
nitrogen metabolism exert influence on each of these levels. However, the type and
degree of influence for most industrial antibiotics are only partially known.
1.1.3 Phosphate Regulation
Phosphate is the crucial growth-limiting nutrient in several antibiotic biosynthetic processes. In candicidin bioproduction with Streptomyces griseus, phosphate levels are depleted about 2 h before the commencement of the production
phase [14]. Phosphate concentration remains low during the entire production
phase of candicidin bioproduction. Addition of 10 mM phosphate at the start of
a candicidin bioproduction prevents depletion of extracellular phosphate. Consequently, growth continues throughout the bioproduction with no antibiotic
production. Phosphate levels are depleted during the growth of Streptomyces
aureofaciens before the production of tetracycline begins. Phosphate in concentrations ranging from 0.3-300 mM usually supports extensive cell growth,
but concentrations of 10 mM and above suppresses biosynthesis of many
antibiotics [1].
7
as the nitrogen source. When the defined media contained both ammonium salts
and proline, the microorganism preferentially utilized the ammonium salts for
growth and proline for novobiocin production. Clearly, a nitrogen regulatory
phenomena controlled the antibiotic production. Similarly, production of
gramicidin S by Bacillus brevis specifically required phenylanaline. In another
report, highest yields of cephalosporin by Streptomyces clavuligerus [6] required
supplementation of medium with certain amino acids and urea.
These examples illustrate two possible circumstances of nitrogen incorporation - (i) including a direct precursor into the antibiotic molecule and (ii)
utilizing the nitrogen atom or a nitrogen group by an antibiotic-specific reaction
on a specific intermediate. In the first case, supplying the production medium
with the direct precursor or a source from which the molecule is easily available
significantly enhances the yield. In the second case, optimizing the medium with
several suitable sources of nitrogen is necessary.
Several routes of nitrogen regulatory phenomena include:
a) Control at the catabolic level.
b) Regulation at the biosynthetic level.
c) Transport of metabolites.
d) Modulation of intracellular concentration of free metabolites.
e) Protein turnover and degradation.
f) Regulation of antibiotic-synthetase formation.
All regulatory mechanisms are manifestations of expression at the genetic
level. Expression of the antibiotic genes depend on many factors, both external
and internal. Nitrogen is just one of the many external factors influencing
these mechanisms. Antibiotic biosynthesis control occurs at the transcription, the
translational and as well as the post translational levels. Regulatory signals from
nitrogen metabolism exert influence on each of these levels. However, the type and
degree of influence for most industrial antibiotics are only partially known.
1.1.3 Phosphate Regulation
Phosphate is the crucial growth-limiting nutrient in several antibiotic biosynthetic processes. In candicidin bioproduction with Streptomyces griseus, phosphate levels are depleted about 2 h before the commencement of the production
phase [14]. Phosphate concentration remains low during the entire production
phase of candicidin bioproduction. Addition of 10 mM phosphate at the start of
a candicidin bioproduction prevents depletion of extracellular phosphate. Consequently, growth continues throughout the bioproduction with no antibiotic
production. Phosphate levels are depleted during the growth of Streptomyces
aureofaciens before the production of tetracycline begins. Phosphate in concentrations ranging from 0.3-300 mM usually supports extensive cell growth,
but concentrations of 10 mM and above suppresses biosynthesis of many
antibiotics [1].