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Antibiotics Antimicrobial agent

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Presentation on theme: "Antibiotics Antimicrobial agent"— Presentation transcript:

1 Antibiotics Antimicrobial agent
chemical substances that are produced by microorganisms which kill or inhibit the growth of other microorganisms (cf. an antibiotic is a chemotherapeutic agent with activity against microorganisms) Penicillin의 놀라운 능력에 감명을 받아 다른 미생물의 성장을 억제하는 유용한 미생물을 흙으로부터 찾기 위해 일생을 바친 Selman A. Waksman과 그의 연구원들은 10,000번 이상의 흙을 배양하는 실 험을 수없이 반복하던 중, 1943년 병든 닭의 목에서 배양된 특이한 미생물이 결핵균의 성장을 억제하는 것을 관찰할 수 있었고, 이 물질을 streptomycin 이라고 명명하였다. Waksman은 흙 속의 곰팡이나 미생물로부터 생성되어 다른 미생물의 성장을 억제하거나 파괴시키는 화학물질을 총칭하여 “antibiotics”라는 용어를 처음으로 사용하였다 Antimicrobial agent Chemical that kills or inhibits the growth of microorganisms

2 Antibiotics products of secondary metabolism
commercially useful antibiotics are produced primarily by filamentous fungi (Penicillium) and by bacteria of the actinomycete group (Streptomyces) and Bacillus most antibiotics employed medically are used to treat bacterial diseases, although a few are known that are effective against fungal diseases

3 Some antibiotics produced commercially Antibiotic
Producing microorganism Bacitracin Bacillus licheniformis (EFB) Cephalosporin cephalosporiumsp (F) Chloramphenicol chemical synthesis (formerly by Streptomyces venezuelae) Cycloheximide Streptomyces griseus Cycloserine Streptomyces orchidaceus Erythromycin Streptomyces erythreus Griseofulvin Penicillium griseofulvin (F) Kanamycin Streptomyces kanamyceticus Lincomycin Streptomyces lincolnensis Neomycin Streptomyces fradiae Nystatin Streptomyces noursei Penicillin Penicillium chrusogenum (F) Polymyxin B Bacillus polymyxa (EFB) Streptomycin Tetracycline Streptomyces rimosus EFB: endospore-forming bacterium; F: fungus; others: actinomycete

4 우리나라 의약품 산업 동향 분석

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6 높은 개발 비용 내성균으로 인한 짧은 항생제 수명

7 Search for New Antibiotics
screening of antibiotic producers testing new microbial isolates for antibiotic production cross-streak method comparison with known antibiotics animal tests for toxicity and therapeutic activity in infected animals clinical test commercial production therapeutic index = toxic dose/therapeutic dose(치료 지수=독성 용량/유효 용량) toxic dose: the drug level at which the agent becomes too toxic for the host therapeutic dose: the drug level required for clinical treatment of a particular infection

8 Isolation using selective media
for streptomyces and identification of antibiotic producers using an indicator organism (지표생물) (eg. Staphylococcus aureus)

9 cross-streak method; Testing an organism for its antibiotic spectrum
of activity

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11 Postmarketing studies

12 commercial production
strain improvement: high-yielding strains which do not produce undesirable side products      mutation/selection, genetic engineering development of fermentation process development of efficient purification system

13 Overall process of extraction and purification of an antibiotic

14 Penicillins Alexander Fleming in 1929 noted that a fungal contaminant (Penicillium notatum) had lysed the bacterial cells on an agar plate of Staphylococcus aureus.

15 Penicillins Fleming found that culture filtrate of P. notatum was effective against many Gram positive bacteria in laboratory conditions, and he even used it to control eye infections. However, he could not purify this compound because of its instability, and it was not until the period of the Second World War ( ) that Florey and Chain, working in the USA, managed to produce the antibiotic on an industrial scale for widespread use. All three scientists shared the Nobel Prize for this work, and rightly so – penicillin rapidly became the "wonder drug" which saved literally millions of lives. It is still a "front line" antibiotic, in common use for some bacterial infections although the development of penicillin-resistance in several pathogenic bacteria now limits its effectiveness.  

16 The action of penicillin is seen in Figure A
The action of penicillin is seen in Figure A. This shows an 'overlay plate', in which a central colony of the fungus Penicillium notatum was allowed to grow on agar for 5-6 days, then the plate was overlaid with a thin film of molten agar containing cells of the yellow bacterium, Micrococcus luteus. The production of penicillin by the fungus has created a zone of growth inhibition of the bacterium. Figure B shows the typical asexual sporing structures of a species of Penicillium

17 Penicillin has an interesting mode of action:
it prevents the cross-linking (transpeptidation) of small peptide chains in peptidoglycan, the main wall polymer of bacteria. Pre-existing cells are unaffected, but all newly produced cells grow abnormally, unable to maintain their wall rigidity, and they are susceptible to osmotic lysis.

18 Bacteria in penicillin solution, 30 min

19 the first β lactam antibiotic discovered, penicillin G, is active primarily
against G+ bacteria. basic structure of penicillins is 6-aminopenicillanic acid (6-APA). variable side chains in position 6

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21 2) biosynthetic penicillins
1) natural penicillins    fermentation is carried out without addition of side-chain precusors.    only benzylpenicillin (penicillin G) is therapeutically useful. 2) biosynthetic penicillins    fermentation is carried out with a side-chain precusor.       penicillin G (phenyl acetic acid), penicillin V (penoxy acetic acid),    penicillin O (allyl mercapto acetic acid) 3) semisynthetic penicillins    another side-chain is coupled chemically to 6-APA (produced from penicillin G chemically or by penicillin acylase).  eg. Ampicillin, have significantly improved medical properties: resistance to stomach acids so that they can be taken orally extended range of activity against some Gram-negative bacteria.

22 Kinetics of the penicillin fermentation with Penicillium chrysogenum
Penicillin G is produced in 40,000 -200,000 liter fermentors. Highly aerobic process. A major ingredient is corn steep liquor. When the carbon source has been nearly exhausted, the penicillin production phase begins. By feeding with various components, the production phase can be extended for several days. Kinetics of the penicillin fermentation with Penicillium chrysogenum

23 Other β lactam antibiotics cephalosporins
produced by Cephalosporium acremonium, low toxicity (less allergenicity) , broad-spectrum antibiotic norcadicin, clavulanic acid, thienamycin Ceftriaxone, a cephalosporin

24 Tetracyclines produced by Streptomyces aureofaciens
broad-spectrum antibiotics interfere with 30S ribosomal subunit function

25 Production scheme for chlortetracycline
with S. aureofaciens more than 300 genes are involved in the production of tetracycline regulation of biosynthesis is complex glucose and phosphate repress the chlortetracycline synthesis

26 Vitamins Vitamin B12 as supplements for human food and animal feeds
more than $700 million per year most vitamins are made commercially by chemical synthesis. Vitamin B12 (cobalamin), B2 (riboflavin): by microbial fermentation Vitamin B12 synthesized in nature exclusively by microorganisms humans must obtain vitamin B12 from food or as vitamin supplement human deficiency: pernicious anemia (악성빈혈): low production of RBCs and nervous system disorder Pseudomonas denitrificans: 60 mg of vitamin B12/liter (molasses as C source)

27 Riboflavin ---> coenzyme FAD and FMN fungus Ashbya gossypii
7 g/liter great economical competition between microbiological process and chemical synthesis

28 Amino acids extensive uses
in food industry (as food and feed additives) in medicine in chemical industry (as starting materials) Glutamic acid as flavor enhancer (monosodium glutamate, MSG)

29 Aspartic acid, phenylalanine ---> aspartame (artificial sweetener)
Aspartame is a nutritive sweetener made by joining two amino acids: L-phenylalanine and L-aspartic acid, with a third component called a methyl ester group. Very little is needed for a sweet taste, making aspartame virtually non-caloric. Relative Sweetness: 180 to 200 times sweeter than sucrose Lysin as food and feed additive Amino acids can be produced microbiologically 1) by direct fermentation 2) by enzymatic synthesis (MO: source of enzyme)

30 Feedback inhibition of lysine synthesis in Brevibacterium flavum

31 How to obtain a mutant cell in which aspartokinase is no longer
(AEC, a lysin analog) How to obtain a mutant cell in which aspartokinase is no longer subject to feedback inhibition positive selection of AEC-resistant mutants: mutagenesis of B. flavum plating on media containing AEC test colonies on plate with AEC ---> 60 g lysine/liter

32 Bioconversion (Biotransformation)
the use of microorganisms to carry out a chemical reaction that is more costly or not feasible nonbiologically 1) culture of cells 2) addition of chemicals to be converted 3) further incubation: chemical reaction 4) purification of desired product major use has been in the production of certain steroid hormones.

33 *Bioconversion has another meaning in Biology
Bioconversion is the conversion of organic materials, such as plant or animal waste, into usable products or energy sources by biological processes or agents, such as certain microorganisms or enzymes. paper, tires, fabric, construction materials, municipal solid waste, sludge, sewage e.g. conversion (by enzymes or microbes) of cellulosic material into sugars which can then be fermented into ethanol

34 Enzyme Production by Microorganisms enzyme
highly specific catalysts: most of the enzymes are used by food industry enzyme produced in the largest amounts are the bacterial proteases, used as additives in laundry detergents

35 High-fructose corn syrup (HFCS)
isoglucose in Europe glucose-fructose in Canada corn syrups that has undergone enzymatic processing to increase its fructose content widely used in processed foods and beverages, including soft drinks, yogurt, cookies, salad dressing and tomato soup is somewhat cheaper than sugar in the United States HFCS 90 (mostly for making HFCS 55), 90% fructose and 10% glucose; HFCS 55 (mostly used in soft drinks), 55% fructose HFCS 42 (used in many foods and baked goods), 42% fructose

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37 production of high-fructose corn syrup
1. thinning reaction by alpha-amylase : starch polysaccharide ---> shortened chain (reduced viscosity) 2. saccharification by glucoamylase: shortened polysaccharide ---> glucose (corn syrup, 100% glucose) 3. isomerization by glucose isomerase: glucose ---> fructose (42%) 4. Enrichment of fructose to 90% by chromatography step

38 Vinegar used as a flavoring ingredients in salads and other foods
ethanol --- acetic acid bacteria ---> acetic acid acetic acid bacteria Acetobacter, Gluconobacter fairly acid tolerant high oxygen demand during growth it is important to ensure sufficient aeration of the medium starting material: wine (wine vinegar in France) beer (malt vinegar in Germany) alcoholic apple juice (cider vinegar in USA) pure alcohol in water (distilled vinegar)

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40 Yeasts in industry eukaryotic micro-organisms classified in the kingdom Fungi. unicellular reproduce asexually by budding yeasts are the most important and the most extensively used microorganisms in industry: Saccharomyces cerevisiae

41 Yeasts in industry Yeast cells Baker's yeast (bread making)
Dried food yeast (food supplements, rich in B vitamins and protein) Dried feed yeast (animal feed) Yeast products Yeast extract (culture media, food additives) B vitamins, Vitamin D Invertase, galactosidase (enzymes for food industry) ATP, NAD, RNA (research biochemicals) Fermentation products Ethanol (for industrial alcohol and as a gasoline extender) Beer, Wine, Whiskey, Brandy, Vodka, Rum

42 Industrial production of yeast cells
(70% moisture) Industrial production of yeast cells


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