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23 Cards in this Set
- Front
- Back
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Antibiotics definition |
Originally defined in the 1940s as:A substance produced by one microorganism which, in low concentrations, inhibit the growth of other microorganisms Current widespread definition:All agents with systemic antimicrobial activity(including synthetic analogues or derivatives of ‘true’ antibiotics, and other chemically synthesized agents that mimic traditional antibiotics in their potency, low toxicity and systemic action) |
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According to this definition, is metronidazolean antibiotic? |
Current widespread definition:All agents with systemic antimicrobial activity(including synthetic analogues or derivatives of ‘true’ antibiotics, and other chemically synthesized agents that mimic traditional antibiotics in their potency, low toxicity and systemic action) |
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The pre-antibiotic era |
-350-550 AD: traces of tetracycline have been found in human skeletal remains from ancient Sudanese Nubia(source was eventually the Nubian beer; grains used to make the fermented drink contained Streptomycesproducing tetracycline) -Ancient Egyptians and Jordanians used beer to treat gum disease -In traditional Chinese medicine a paste from chewed barley and mouldyapple was used on surface of wounds -Mouldycorn soaked in water is mentioned as a therapeutic in the Jewish Talmud -In 1640, London apothecary and King‘s herbalist John Parkington suggests that moulds have a curative effect when applied to infections -In 1897, Ernest Duchesne healed infected guinea pigs from typhoid using mould -In 1893, BartolomeoGosio purified my cophenolic acid from Penicillium and showed it was able to inhibit the grow of Bacillus anthracis (work rarely recognised, maybe because was only written in Italian) -In 1909, Paul Ehrlich discovered arsphenamine (the first synthetic antibiotic as a treatment for syphilis) |
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The start of the antibiotic era |
-Fleming discovered penicillin in 1929 -Development work was undertaken at Oxford University over the next 10 years -The American pharmaceutical industry converted the discovery into a medicine manufactured on a large scale(to treat battlefield-acquired infections during 2ndWorld War and also gonorrhoea) -Benzylpenicillin was the original antibiotic -In the late 1940s and early 1950s, it was joined by other penicillins and by other classes of antibiotics(such as tetracyclines, macrolidesand aminoglycosides) -All of these were ‘true’ antibiotics in traditional sense(i.e., extracted from large-volume cultures of Streptomycesor fungi) |
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Microbial sources of antibiotics |
- Bacitracinand polymyxinare obtained from some Bacillusspecies -Gentamicinis obtained from Micromonosporapurpurea -Monobactamsare obtained from Pseudomonas acidophilaand Gluconobacterspecies -Griseofulvinand some penicillinsand cephalosporinsfrom certain fungal genera such as Penicilliumand Acremonium -Streptomycin, tetracyclines, etc. are obtained from Streptomycesspecies (most antibiotics have been produced from Streptomyces) |
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Pharmaceutical industry and antibiotics |
-In the 1960s we saw the advent of semi-synthetic antibiotics (penicillinsparticularly; naturally occurring substances were extracted from microbial cultures, purified and then modified by conventional chemical reactions) -Since then, an increasing number of antibiotics have been totally synthesized |
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Antibiotic susceptibility and resistance |
The antibiotic discovery void, together with the increase in antibiotic resistance, has led to the realization that some infections may soon become untreatable There is an urgent need to preserve the current antibiotics |
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Why there are no new antibiotics? |
-No money in them (short period of use; official advice to use them sparingly) -Organisms become resistant eventually (so most antibiotics become less useful as time goes by) -Cost of development (now typically 1.5 billion USD for a genuinely new drug) -Difficulty of constructing FDA criteria-satisfying clinical trials |
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How do scientists can traditionally find new antibiotics? |
-Nature is the best source of new drugs -Screen for antibiotic producing microbes |
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Screen for antibiotic producing microbes |
-Spread a soil dilution on a plate of selective medium -Sterile glass spreader -Incubate -Colonies may appear -Overlay with an indicator organism incubate -Nonproducing organisms don't have zones of growth inhibition. producing organisms do Look at slide 20+21 (know what each species looks like) |
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What to do after finding a new antibiotic producing microbe? |
Purify and analyze the antimicrobial agent (e.g. structure/function tests; eventually modify chemical structure to enhance antimicrobial activity or decrease toxicity in humans) If the new antibiotic is biologically active in vivo, the producing strain may be genetically modified to increase yields to levels acceptable for commercial development(e.g. by recombinant DNA technology) |
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Chemical modification of natural antibiotics (the example of penicillins) |
Slide 23 |
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Naturally occurring penicillins + examples |
e.g. those produced by fermentation of moulds (such as Penicillium notatumand P. chrysogenum) -Most important examples are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V) + look at slide 24 |
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Semisyntheticpenicillins |
In 1959, scientists succeeded in isolating the penicillin ‘nucleus ’ (6-aminopenicillanic acid; 6-APA) Acylationof 6-APA with appropriate functional groups results in new penicillins + look at diagram on slide 25 +26 |
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Industrial antibiotic production |
Industrial manufacture of most antibiotics is based on the large scale production of microorganisms which convert raw materials into antibiotics Process commonly referred to as a fermentation -Traditionally, fermentations are biological processes occurring in the absence of oxygen -However, the term is now commonly applied to any large scale cultivation of microorganisms(whether aerobic -with oxygen, or anaerobic -without oxygen) -Main types of fermentation processes are: Batch and fed-batch fermentations and Continuous fermentations |
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Batch fermentation |
-Partially closed system in which most of the materials required are loaded onto the fermentation vessel (sterilisedbefore the process starts and removed at the end) -During the course of a batch fermentation there is gas exchange and pH may be controlled -Conditions are continuously changing with time(but in a well-mixed reactors, conditions are uniform throughout the reactor at any instant time) |
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Fed-batch fermentation |
Cells are grown under a batch regime for some time(usually until close to the end of the exponential growth phase) At this point, reactor is fed with a solution of substrates(without the removal of culture fluid) |
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Continuous fermentation |
-Technique involving feeding the microorganism used for the fermentation with fresh sterile nutrients -At the same time, spent medium plus cells are removed from the system -A time-independent steady-state can be attained(growth rate can be held at an optimum for product fermentation) -One advantage is long fermentation runs of many weeks, hence greater productivity per vessel(but occurrence of contaminations may be an issue) -Suitable for products whose synthesis is proportional to cell density and actively growing cultures(e.g. products such as alcohols and organic acids produced during the exponential growth phase) -Not generally an economical process where synthesis is not associated with growth(and where strain degeneration may be a concern; e.g. products produced during the stationary phase) |
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Primary and secondary metabolites |
Primary metabolites, such as ethanol, are produced during active cell multiplication(mostly during the exponential growth phase)Secondary metabolites, such as antibiotics, are produced near or on the stationary phase+ slide 34 |
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Whichfermentation processes are more suitable for antibiotic production? |
Most antibiotics are produced with the fed-batch system (e.g., teicoplanin, daptomycin, B-lactams) Continuous culture uncommon in pharmaceutical industry For the majority of antibiotics, the only feasible supply process continues to be fermentation(full chemical synthesis is either too complicated or too expensive) Most antibiotics introduced into the market since 2000 are microbial products and are still produced by fermentation processes |
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Industrial antibiotic production steps |
In a fed-batch fermentation, sterile medium in a vessel is inoculated and the broth fermented for a defined period(e.g., days or weeks) During fermentation, nutrients, antifoam agents and air are supplied, pH is controlled and exhaust gases removed After fermentation, the tank is emptied and the broth extracted by downstream processing to yield antibiotic(after emptying, the tank is cleaned and prepared for a new batch) Following fermentation, antibiotics are recovered, concentrated and purified by a series of downstream processing stages Depending on the specific antibiotic, the fermentation broth is processed by various purification methods(e.g., to purify an oil-soluble antibiotic such as penicillin, a solvent extraction method may be used; the broth is treated with organic solvents which can specifically dissolve the antibiotic) For semi-synthetic antibiotics there will be a chemical conversion stage to produce the bulk antibiotic The bulk antibiotic is then formulated into the required dosage form(e.g. tablets, vials for injection, solutions, ointments) Stages up to bulk antibiotic are commonly termed primary manufacture Stages from bulk antibiotic to formulated product are termed secondary manufacture |
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Process of penicillin production |
slide 41 |
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Summary |
Most antibiotics used today have a natural origin(they are produced by microorganisms; semi-synthetic antibiotics are chemically modified natural antibiotics) The antibiotic discovery void, together with the increase in antibiotic resistance, has led to the realization that some infections may soon become untreatable Industrial manufacture of most antibiotics is based on the large scale production of microorganisms by fermentation processes Most antibiotics are produced with fed-batch fermentation systems |
