24. Antibiotics. Now most of the antibiotics were discovered from soil microorganisms especially in microorganism Streptomyces spp. Engineered genes into production strains. Modification of existing antibiotics.
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Secondary metabolites (idiolites) are produced from
Substrates provided by primary metabolism.
COMMERCIAL PRODUCTION OF PENICILLIN
Originally used Penicillium notatum , now use Penicillium chrysogenum.
Initially produced via surface mat culture.
Inefficient, slow penicillin synthesis and contamination.
3. Carbon and nitrogen sources are depleted, antibiotic production ceases, the mycelia lyse releasing ammonia and the pH rises.
Composition of early media%
corn steep liquor (cotton seeds, peanut,
Linseed or soybean meals)2-4
lactose, glucose or beet molasses2-4
CaCO3 or phosphates (buffer)0.5-1
Catabolite repression of the enzymes responsible for penicillin biosynthesis occurs in high concentrations of glucose.
Use of precursors to increase penicillin yield.
Use of precursors:
(a) it can be reacted with a calcium carbonate slurry to give the calcium salt which may be filtered, lyophilized or spray dried.
(b) it may be reacted with sodium or potassium buffers to give the salts of these metals which can also be freeze or spray dried;
(c) it may be precipitated with an organic base such as triethylamine.
Chemical and Enzymatic Deacylation
of Penicillins to 6-APA
Penicillin V or G
[R=Ph or PhO]
6-Aminopenicillanic Acid (6-APA)
6-APA:Raw material for production of new semisynthetic penicillins (amoxycillin and ampicillin)
Fewer side effects
Greater selectivity against pathogens
Broader antimicrobial range including G- -ve
Improved pharmacological properties
Gastric acid stability & oral absorbability
Resistance to beta-lactamases
6-Aminopenicillanic Acid (6-APA)
Use of hazardous chemicals - pyridine, phosphorous
pentachloride, nitrosyl chloride
Regio- and stereo-specific
Mild reaction conditions (pH 7.5, 37 oC)
Enzymatatic process is cheaper by 10%
Penicillin G acylase (PGA)- Escherichia coli, Bacillus megaterium,
Penicillin V acylases (PVA)- Beijerinckia indica var. Penicillium,
Fusarium sp., Pseudomonas acidovorans
Life, 500-2880 hours
6 - APA
Side Chain Modification
Isolation or collection of cultures
Screening of cultures to detect those with antimicrobial activity
Development of methods for submerged-culture production
Development of methods for isolation and purification of antibiotic
Determination of antibiotic properties (physical: adsorption and absorption, chemical: reactions, solubility in solvents, stability to acids, alkalis, heat etc.)
Evaluation of antibiotic
Comparison with existing antibiotic
Development of pilot plant production methods
Submission of licence for clinical trials
Testing of purified antibiotic
Development of plant scale production methods
Obtaining a product licence for clinical use
Development of methods to control production of antibiotic
Development of new applications
Development of marketing and distribution system
Financing of business
Several methods have been employed in primary screening.
(iv) Further laboratory evaluation:
(v) Pilot plant production:
(vi) Plant production:
(viii) Marketing and financing