Penicillin

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Penicillin core structure, where "R" is the variable group. Penicillin (sometimes abbreviated PCN or pen) is a group of antibiotics derived from Penicillium fungi.[1] They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis, and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are -lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.

Contents
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1 Medical uses 2 Adverse effects 3 Mechanism of action 4 Structure 5 Biosynthesis 6 Production 7 History o 7.1 Discovery o 7.2 Medical application o 7.3 Mass production o 7.4 Unethical experimentation o 7.5 Developments from penicillin 8 See also 9 References 10 External links

[edit] Medical uses

The term "penicillin" is often used generically to refer to benzylpenicillin (penicillin G), procaine benzylpenicillin (procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), and phenoxymethylpenicillin (penicillin V). Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period. Phenoxymethylpenicillin is less active against Gramnegative bacteria than benzylpenicillin.[2][3] Benzylpenicillin, procaine penicillin and benzathine penicillin are given by injection (parenterally), but phenoxymethylpenicillin is given orally.

[edit] Adverse effects

Main article: Penicillin drug reaction Common adverse drug reactions (1% of patients) associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverse effects (0.11% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and pseudomembranous colitis.[4]

[edit] Mechanism of action

Main article: Beta-lactam antibiotic

Penicillin and other -lactam antibiotics act by inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.

Bacteria that attempt to divide in the presence of penicillin fail to do so and end up shedding their cell walls in the process. Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. -Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, but have no direct effect on cell wall degradation. The -lactam moiety (functional group) of penicillin binds to the enzyme (DDtranspeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due to osmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the bacteria's existing peptidoglycan. This imbalance between cell wall production and degradation is responsible for the rapid cell-killing action of this class of drugs, even in the absence of cell division. In addition, the relatively small size of the penicillin molecule allows it to penetrate deeply into the cell wall, affecting its entire depth. This is in contrast to the other major class of anitbiotics that inhibit cell wall synthesis, the glycopeptide antibiotics (which includes vancomycin and teicoplanin).

Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin.[citation needed] Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms. Penicillins, like other -lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants.[5]

[edit] Structure

Chemical structure of Penicillin G

Penicillin core structure, in 3D. Purple areas are variable groups. The term "penam" is used to describe the core skeleton of a member of the penicillin antibiotics. This skeleton has the molecular formula R-C9H11N2O4S, where R is a variable side chain. Normal penicillin has a molecular weight of 313[6] to 334[7][8] g/mol (latter for penicillin G). Penicillin types with additional molecular groups attached may have a molar mass around 500 g/mol. For example, cloxacillin has a molar mass of 476 g/mol and dicloxacillin has a molar mass of 492 g/mol.[9]

[edit] Biosynthesis

Penicillin biosynthesis Overall, there are three main and important steps to the biosynthesis of penicillin G (benzylpenicillin).

The first step is the condensation of three amino acids L--aminoadipic acid, Lcysteine, L-valine into a tripeptide.[10][11][12] Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine.[13][14] The condensed tripeptide is named -(L--aminoadipyl)-L-cysteine-D-valine (ACV). The condensation reaction and epimerization are both catalyzed by the enzyme -(L-aminoadipyl)-L-cysteine-D-valine synthetase (ACVS), a nonribosomal peptide synthetase or NRPS. The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which is encoded by the gene pcbC.[10][11] Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.[13] The final step is an transamidation by isopenicillin N N-acyltransferase, in which the aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.[10]

[edit] Production
Penicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin. -ketoglutarate + AcCoA homocitrate L--aminoadipic acid L-lysine + -lactam

The by-product, L-lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production. The Penicillium cells are grown using a technique called fed-batch culture, in which the cells are constantly subject to stress, which is required for induction of penicillin production. The available carbon sources are also important: Glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled. The biotechnological method of directed evolution has been applied to produce by mutation a large number of Penicillium strains. These techniques include error-prone PCR, DNA shuffling, ITCHY, and strand-overlap PCR. Semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.

[edit] History
[edit] Discovery
Main article: History of penicillin The discovery of penicillin is attributed to Scottish scientist and Nobel laureate Alexander Fleming in 1928.[15] He showed that, if Penicillium notatum were grown in the appropriate substrate, it would exude a substance with antibiotic properties, which he dubbed penicillin. This serendipitous observation began the modern era of antibiotic discovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate Howard Walter Florey, together with the German Nobel laureate Ernst Chain and the English biochemist Norman Heatley. However, several others reported the bacteriostatic effects of Penicillium earlier than Fleming. The use of bread with a blue mould (presumed to be Penicillium) as a means of treating suppurating wounds was a staple of folk medicine in Europe since the Middle Ages.[citation needed] The first published reference appears in the publication of the Royal Society in 1875, by John Tyndall.[16] Joaquim Monteiro Caminho, Professor of Botany and Zoology of the Faculty of Medicine of Rio de Janeiro, Brazil, also recognised the antibiotic activity of Penicillium and other fungi in 1877. In his book, "Elements of General and Medical Botany" (under a section titled 'Useful fungi, harmful and curious'), he stated: O bolor (Penicillium infestans, Penicillium glaucum, fig 1680, Ascophora e tantos outros) util porque nutre-se decompondo e destruindo as materias organicas em putrefaco, e de modo que o cheiro infecto no se produz, em via de regra, ou produz-se em propores infinitamente menores. [Translation: "The mould (Penicillium infestans, Penicillium glaucum, figure 1680, Ascophora and many others) is useful because it feeds on decaying organic matter and destroys putrifaction so that, as a rule, the odour of infection does not occur, or is produced in infinitely smaller amounts."][17]

Ernest Duchesne documented it in an 1897 paper, which was not accepted by the Institut Pasteur because of his youth. In March 2000, doctors at the San Juan de Dios Hospital in San Jos, Costa Rica, published the manuscripts of the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (18871944). They reported Picado's observations on the inhibitory actions of fungi of the genus Penicillium between 1915 and 1927. Picado reported his discovery to the Paris Academy of Sciences, yet did not patent it, even though his investigations started years before Fleming's. Joseph Lister was experimenting with Penicillum in 1871 for his aseptic surgery. He found that it weakened the microbes, but then he dismissed the fungi. These early investigations did not lead to the use of antibiotics to treat infection because they took place in obscure circumstances, and the idea that infections were caused by transmissible agents was not widely accepted at the time. Sterilization measures had been shown to limit the outbreak and spread of disease; however, the mechanism of transmission of disease by parasites, bacteria, viruses and other agents was unknown. In the late 19th century, there was increasing knowledge of the mechanisms by which living organisms become infected, how they manage infection once it has begun and, most importantly in the case of penicillin, the effect that natural and man-made agents could have on the progress of infection. Fleming recounted that the date of his discovery of penicillin was on the morning of Friday, September 28, 1928.[18] It was a fortuitous accident: in his laboratory in the basement of St. Mary's Hospital in London (now part of Imperial College), Fleming noticed a Petri dish containing Staphylococcus plate culture he mistakenly left open, was contaminated by blue-green mould, which formed a visible growth. There was a halo of inhibited bacterial growth around the mould. Fleming concluded that the mould released a substance that repressed the growth and lysing the bacteria. He grew a pure culture and discovered it was a Penicillium mould, now known to be Penicillium notatum. Charles Thom, an American specialist working at the U.S. Department of Agriculture, was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mould. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, and noted its laboratory value in the isolation of Bacillus influenzae (now Haemophilus influenzae).[19] After further experiments, Fleming was convinced penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying it after 1931. He restarted clinical trials in 1934, and continued to try to get someone to purify it until 1940.[20]

[edit] Medical application

Florey (pictured), Fleming and Chain shared a Nobel Prize in 1945 for their work on penicillin. In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to use penicillin to treat sycosis barbae, eruptions in beard follicles, but was unsuccessful, probably because the drug did not penetrate the skin deeply enough. Moving on to ophthalmia neonatorum, a gonococcal infection in infants, he achieved the first recorded cure with penicillin, on November 25, 1930. He then cured four additional patients (one adult and three infants) of eye infections, failing to cure a fifth.[21] In 1939, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Boris Chain, Arthur Duncan Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed because of insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved it harmless and effective on mice.[22] Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford, England. These trials continue to be cited by some sources as the first cures using penicillin, though the Paine trials took place earlier.[21] On March 14, 1942, John Bumstead and Orvan Hess saved a dying patient's life using penicillin.[23][24]

[edit] Mass production

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945[chronology citation needed]. Penicillin has since become the most widely used antibiotic to date, and is still used for many Gram-positive bacterial infections. A team of Oxford research scientists led by Australian Howard Florey and including Ernst Boris Chain and Norman Heatley devised a method of mass-producing the drug. Florey and Chain shared the 1945 Nobel Prize in Medicine with Fleming for their work. After World War II, Australia was the first country to make the drug available for civilian use. Chemist John C. Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production.

The challenge of mass-producing this drug was daunting. On March 14, 1942, the first patient was treated for streptococcal septicemia with U.S.-made penicillin produced by Merck & Co.[25] Half of the total supply produced at the time was used on that one patient. By June 1942, there was just enough U.S. penicillin available to treat ten patients.[26] In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe.[27] A mouldy cantaloupe in a Peoria, Illinois, market in 1943 was found to contain the best and highest-quality penicillin after a worldwide search.[28] The discovery of the cantaloupe, and the results of fermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. Large-scale production resulted from the development of deep-tank fermentation by chemical engineer Margaret Hutchinson Rousseau.[29] As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.[27]

Penicillin was being mass-produced in 1944. G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin.[30] During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%15% of lives.[citation needed] Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug, necessitating frequent dosing. Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration. Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused.[31] This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-

production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.[31] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[4]

[edit] Unethical experimentation

In a 1946 to 1948 study in Guatemala, U.S. researchers used prostitutes to infect prison inmates, insane asylum patients, and Guatemalan soldiers with syphilis and other sexually transmitted diseases (STDs), to test the effectiveness of penicillin in treating such diseases. They later tried infecting people with "direct inoculations made from syphilis bacteria poured into the men's penises and on forearms and faces that were slightly abraded ... or in a few cases through spinal punctures".[32] Approximately 1300 people were infected as part of the study (including orphaned children). The study was sponsored by the Public Health Service, the National Institutes of Health and the Pan American Health Sanitary Bureau (now the World Health Organization's Pan American Health Organization) and the Guatemalan government. The team was led by John Charles Cutler, who later participated in the Tuskegee syphilis experiments. Cutler chose to do the study in Guatemala because he would not have been permitted to do it in the United States.[33][34][35][36] The Presidential Commission for the Study of Bioethical Issues determined that 83 people died; however, it was not possible to determine whether the experiments were the direct cause of death. [37]

[edit] Developments from penicillin

The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance). The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded -lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against -lactamase-producing bacterial species, but were ineffective against the methicillinresistant Staphylococcus aureus (MRSA) strains that subsequently emerged. Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the -lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most important, the cephalosporins, still retain it at the center of their structures.[38]

[edit] See also

Wikimedia Commons has media related to: Penicillin antibiotics

-Lactam antibiotic Drug allergy History of penicillin Penicillinase

[edit] References
1. ^ "penicillin" at Dorland's Medical Dictionary[dead link] 2. ^ Garrod, L. P. (1960). "Relative Antibacterial Activity of Three Penicillins.". British Medical Journal (5172): 52729. 3. ^ Garrod, L. P. (1960). "The Relative Antibacterial Activity of Four Penicillins.". British Medical Journal (5214): 16956. 4. ^ a b Rossi S, editor, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. 5. ^ Kasten, Britta; Reski, Ralf (30 March 1997). "-lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon esculentum)". Journal of Plant Physiology 150 (12): 137140. 6. ^ learnchem.net Stoichiometry Section: Percent Mass. By Takalah. Retrieved on Jan 9, 2009 7. ^ Drug Safety > Penicillin G Retrieved on Jan 9, 2009 8. ^ SymplusWiki > penicillin G Retrieved on Jan 9, 2009 9. ^ Barbosa S., Taboada P., Ruso J.M., Attwood D., Mosquera V. (August 2003). "Complexes of penicillins and human serum albumin studied by static light scattering". Colloids and Surfaces A: Physicochemical and Engineering Aspects 224 (13): 2516. doi:10.1016/S0927-7757(03)00322-4. 10. ^ a b c Al-Abdallah, Q., Brakhage, A. A., Gehrke, A., Plattner, H., Sprote, P., Tuncher, A. (2004). "Regulation of Penicillin Biosynthesis in Filamentous Fungi". In Brakhage AA. Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases. pp. 4590. doi:10.1007/b99257. ISBN 3-540-22032-1. 11. ^ a b Brakhage, A. A. (1998). "Molecular Regulation of -Lactam Biosynthesis in Filamentous Fungi". Microbiol Mol Biol Rev. 62 (3): 54785. PMC 98925. PMID 9729600. 12. ^ Baldwin, J. E., Byford, M. F., Clifton, I., Hajdu, J., Hensgens, C., Roach, P, Schofield, C. J. (1997). "Proteins of the Penicillin Biosynthesis Pathway". Curr Opin Struct Biol. (7): 85764. 13. ^ a b Fernandez, F. J., Fierro, F., Gutierrez, S, Kosalkova, K . Marcos, A. T., Martin, J. F., Velasco, J. (September 1994). "Expression of Genes and Processing of Enzymes for the Biosynthesis of Penicillins and Cephalosporms". Anton Van Lee 65 (3): 22743. doi:10.1007/BF00871951. PMID 7847890. 14. ^ Baker, W. L., Lonergan, G. T. "Chemistry of Some Fluorescamine-Amine Derivatives with Relevance to the Biosynthesis of Benzylpenicillin by Fermentation". J Chem Technol Biot. 2002, 77, pp1283-1288. 15. ^ "Alexander Fleming Time 100 People of the Century". Time. "It was a discovery that would change the course of history. The active ingredient in that mold, which Fleming named penicillin, turned out to be an infection-fighting agent of enormous potency. When

it was finally recognized for what it is the most efficacious life-saving drug in the world penicillin would alter forever the treatment of bacterial infections." 16. ^ Phil. Trans., 1876, 166, pp27-74. Referred to at: Discoveries of anti-bacterial effects of penicillium moulds before Fleming 17. ^ J.M. Caminho, 'Cogumlos uteis, nocivos e curiosos.' In: Elementos de Botnica geral e mdica, 1877, p1718. Published in 5 vols, Typographia Nacional, Rio de Janeiro, Brazil. (Reported by Prof P.R. Chocair as held at the Biblioteca da Cmara Municipal de So Paulo, Brasil) 18. ^ Haven, Kendall F. (1994). Marvels of Science : 50 Fascinating 5-Minute Reads. Littleton, Colo: Libraries Unlimited. pp. 182. ISBN 1-56308-159-8. 19. ^ Fleming A. (1929). "On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenz". Br J Exp Pathol 10 (31): 22636. 20. ^ Brown, Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN 0-7509-3152-3. 21. ^ a b Wainwright M, Swan HT (January 1986). "C.G. Paine and the earliest surviving clinical records of penicillin therapy". Medical History 30 (1): 4256. PMC 1139580. PMID 3511336. 22. ^ Drews, Jrgen (March 2000). "Drug Discovery: A Historical Perspective". Science 287 (5460): 19604. doi:10.1126/science.287.5460.1960. PMID 10720314. 23. ^ Saxon, W. (June 9, 1999). "Anne Miller, 90, first patient who was saved by penicillin". The New York Times. 24. ^ Krauss K, editor (1999). "Yale-New Haven Hospital Annual Report" (PDF). New Haven: Yale-New Haven Hospital. 25. ^ The First Use of Penicillin in the United States, by Charles M. Grossman. Annals of Internal Medicine 15 July 2008: Volume 149, Issue 2, Pages 135-136. 26. ^ John S. Mailer, Jr., and Barbara Mason. "Penicillin : Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois". lib.niu.edu. Retrieved 2008-02-11. 27. ^ a b John Parascandola (1980). The History of antibiotics: a symposium. American Institute of the History of Pharmacy No. 5. ISBN 0-931292-08-5. 28. ^ Mary Bellis. "The History of Penicillin". Inventors. About.com. Retrieved 2007-10-30. 29. ^ Chemical Heritage Manufacturing a Cure: Mass Producing Penicillin 30. ^ "ExplorePAhistory.com". Retrieved 2009-05-11. 31. ^ a b Silverthorn, DU. (2004). Human physiology: an integrated approach. (3rd ed.). Upper Saddle River (NJ): Pearson Education. ISBN 0-8053-5957-5. 32. ^ Michael Cook (02 Oct 2010). "US apologizes for 1940s unethical research in Guatemala". BioEdge. 33. ^ "U.S. sorry for Guatemala syphilis experiment". CBC News. October 1, 2010. 34. ^ Rob Stein (October 1, 2010). "U.S. apologizes for newly revealed syphilis experiments done in Guatemala". Washington Post. 35. ^ "US sorry over deliberate sex infections in Guatemala". BBC News. October 1, 2010. 36. ^ Chris McGreal (October 1, 2010). "US says sorry for 'outrageous and abhorrent' Guatemalan syphilis tests". Guardian (London). 37. ^ Rob Stein (August 30, 2011). "U.S. scientists knew 1940s Guatemalan STD studies were unethical, panel finds". Washington Post (?).

38. ^ James, PharmD, Christopher W.; Cheryle Gurk-Turner, RPh (2001 January). "Crossreactivity of beta-lactam antibiotics". Baylor University Medical Center Proceedings (Dallas, Texas: Baylor University Medical Center) 14 (1): 1067. PMC 1291320. PMID 16369597.

[edit] External links

The production of penicillin N and cephalosporin C by two mutants of a Cephalosporium sp. has been studied with cultures grown in a chemically defined medium and with suspensions of washed mycelium in water or a buffered salt solution. 2. Antibiotic synthesis began at an early stage of growth and its rate per unit weight of mycelium appeared to pass its maximum as morphological changes were occurring in young hyphae. This rate subsequently declined, but rapid production could continue after net growth had ceased. 3. In a series of shake-flask fermentations in the growth medium, increases in the yield of penicillin N above the mean were correlated with much smaller increases in the yield of cephalosporin C and vice versa. 4. In suspensions of washed mycelium, moderate decreases in the efficiency of aeration increased the yield of penicillin N and decreased that of cephalosporin C. A similar result normally followed the addition of methionine to the suspension fluid, and in both cases there was usually an increase in the yield of the two antibiotics combined. 5. The apparent intracellular concentrations of the antibiotics were much lower than those attained extracellularly and also much lower than those of most of the amino acids in the intracellular pool. No detectable amount of [(14)C]penicillin N added to the extracellular fluid was found to enter the mycelium. 6. Very small amounts of peptide material whose behaviour was similar to that of the sulphonic acid of delta-(alpha-amino-adipoyl)cysteinylvaline on paper electrophoresis at pH1.8 were found in extracts of the mycelium that had been oxidized with performic acid. 6-Aminopenicillanic acid and 7-aminocephalosporanic acid were not detected. 7. Ultrasonic treatment of the mycelium resulted in rapid fragmentation of mycelial chains, rupture of many individual cells, and the liberation of amino acids and other substances into the medium. 8. Ultrasonically treated preparations synthesized penicillin N and cephalosporin C rapidly after a lag of 12hr. Antibiotic synthesis was accompanied by the growth of hyphae from swollen mycelial fragments and by the re-establishment of permeability barriers resulting in the uptake of amino acids from the medium.

bstract
The discovery of penicillin was announced over 60 years ago. It was the first beta-lactam antibiotic and the importance of this group is greater today than it has ever been. It is clear that even at 60 years of age, beta-lactams are going strong and no one contemplates their early retirement. Currently, sales of beta-lactam compounds form the largest share by far of the world's antibiotic market. The beta-lactam antibiotics include penicillins such as penicillin G, penicillin V, ampicillin, cloxacillin, and piperacillin; cephalosporins such as cephalothin, cephaloridine, cephalexin, and cefaclor; and cephamycins such as cefoxitin. In addition, betalactam antibiotics include the more recently developed nonclassical structures such as

monobactams, including aztreonam; clavulanic acid, which is a component of the combination drug augmentin; and thienamycin, which is chemically transformed into imipenem, a component of the combination drug known as primaxin (or tienam). The classical beta-lactam antibiotics can be divided into hydrophobic and hydrophilic fermentation products. The hydrophobic members, e.g. benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V), contain non-polar side chains, e.g. phenylacetate and phenoxyacetate, respectively, and are made only by filamentous fungi; the best known of these is Penicillium chrysogenum. The antibacterial spectrum of the hydrophobic penicillins is essentially Gram-positive. The hydrophilic types are penicillin N, cephalosporins and 7-alpha-methoxycephalosporins (cephamycins) which are made by fungi, actinomycetes and unicellular bacteria. They all contain the polar side chain, D-alphaaminoadipate. We can draw a sequence of reactions which describes the biosynthesis of all penicillins and cephalosporins, however the total sequence exists in no one microorganism. All penicillin and cephalosporin biosynthetic pathways possess the first three steps in common and all cephalosporin pathways go through deacetylcephalosporin C. However, there are many subsequent biosynthetic reactions which vary in the different producing organisms. Production of beta-lactam antibiotics occurs best under conditions of nutrient imbalance and at low growth rates. Nutrient imbalance can be brought about by limitation of the carbon, nitrogen or phosphorus source. In addition to these factors, amino acids such as lysine and methionine exert marked effects on production of penicillins and/or cephalosporins by some microorganisms. Induction of some of the synthetases, especially the first enzyme, ACV synthetase, by methionine is the basis of the methionine stimulation of cephalosporin C synthesis in C. acremonium. Inhibition of homocitrate synthase is the mechanism involved in lysine inhibition of penicillin synthesis in Penicillium chrysogenum.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1815263 [PubMed - indexed for MEDLINE]