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Penicillin

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For the Japanese band, see Penicillin (band).
Penicillin core structure. The "R" is the variable group.

Penicillin (sometimes abbreviated PCN or pen) is a group of antibiotics derived from Penicillium fungi.[1] Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilis and Staphylococcus infections. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are Beta-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.

The term "penicillin" can also refer to the mixture of substances that are naturally, and organically, produced.[2]

Structure

Penicillin core structure, in 3D. Purple areas are variable groups.

The term "penam" is used to describe the core skeleton of a member of a penicillin antibiotic. This skeleton has the molecular formula R-C9H11N2O4S, where R is a variable side chain.

Normal penicillin has a molecular weight of 313[3] to 334[4][5] 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.[6]

Biosynthesis

Penicillin biosynthesis.

Overall, there is a total of three main and important steps to the biosynthesis of penicillin G (benzylpenicillin)

  • The first step in the biosynthesis of penicillin G is the condensation of three amino acids L-α-aminoadipic acid, L-cysteine, L-valine into a tripeptide.[7][8][9] Before condensing into a tripeptide, the amino acid L-valine will undergo epimerization and become D-valine.[10][11] After the condensation, the tripeptide is named δ-(L-α-aminoadipyl)-L-cysteine-D-valine, which is also known as ACV. While this reaction occurs, we must add in a required catalytic enzyme ACVS, which is also known as δ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase. This catalytic enzyme ACVs is required for the activation of the three amino acids before condensation and the epimerization of transforming L-valine to D-valine.
  • The second step in the biosynthesis of penicillin G is to use an enzyme to change ACV into isopenicillin N. The enzyme is isopenicillin N synthase with the gene pcbC enclosed. The tripeptide on the ACV will then undergo oxidation, which then allows a ring closure so that a bicyclic ring is formed.[7][8] Isopenicillin N is a very weak intermediate because it does not show much antibiotic activity.[10]
  • The Last step in the biosynthesis of penicillin G is the exchange the side-chain group so that isopenicillin N will become penicillin G. Through the catalytic coenzyme isopenicillin N acyltransferase (IAT), the alpha-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.[7]

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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 beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were significant for their activity against beta-lactamase-producing bacteria species, but are ineffective against the methicillin-resistant Staphylococcus aureus 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 beta-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.[12]

Mechanism of action

Main article: Beta-lactam antibiotic

β-Lactam antibiotics work by inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, 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.

Gram-positive bacteria are called protoplasts when they lose their cell wall. Gram-negative bacteria do not lose their cell wall completely and are called spheroplasts after treatment with penicillin.

Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.

Penicillins, like other β-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.[13]

Variants in clinical use

The term "penicillin" is often used in the generic sense to refer to one of the narrow-spectrum penicillins, in particular, benzylpenicillin (penicillin G).

Other types include:

Adverse effects

Main article: Penicillin drug reaction

Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and pseudomembranous colitis.[15]

Production

Penicillin is a secondary metabolite of fungus Penicillium that 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.

α-ketoglutarate + AcCoA → homocitrate → L-α-aminoadipic acid → L-Lysine + β-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 and will produce plenty of penicillin. The carbon sources that are available are also important: Glucose inhibits penicillin, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must be controlled automatically.

Penicillin production emerged as an industry as a direct result of World War II. During the war, there was an abundance of jobs available in the U.S. on the home front. The War Production Board was founded to monitor job distribution and production.[16] Penicillin was produced in huge quantities during the war and the industry prospered. In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. At the time of this plan, 425 million units per year were being produced. As a direct result of the war and the War Production Board, by June 1945 over 646 billion units per year were being produced.[17]

In recent years, the biotechnology method of directed evolution has been applied to produce by mutation a large number of Penicillium strains. These directed-evolution techniques include error-prone PCR, DNA shuffling, ITCHY, and strand overlap PCR.

See also

Wikimedia Commons has media related to Penicillin antibiotics.

References

  1. ^ "penicillin" at Dorland's Medical Dictionary
  2. ^ "penicillin - Definition from Merriam-Webster's Medical Dictionary". Retrieved 2009-01-02.
  3. ^ learnchem.net Stoichiometry Section: Percent Mass. By Takalah. Retrieved on Jan 9, 2009
  4. ^ Drug Safety > Penicillin G Retrieved on Jan 9, 2009
  5. ^ SymplusWiki > penicillin G Retrieved on Jan 9, 2009
  6. ^ Barbosa S., Taboada P., Ruso J.M., Attwood D., Mosquera V. (2003). "Complexes of penicillins and human serum albumin studied by static light scattering". Colloids and Surfaces A: Physicochemical and Engineering Aspects. 224: 251–6. doi:10.1016/S0927-7757(03)00322-4. {{cite journal}}: Unknown parameter |issues= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ 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 (ed.). Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases. pp. 45–90. doi:10.1007/b99257. ISBN 3-540-22032-1.{{cite book}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Brakhage, A. A. (1998). "Molecular Regulation of b-Lactam Biosynthesis in Filamentous Fungi". Microbiol Mol Biol Rev. (62): 547–85.
  9. ^ 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): 857–64.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b Fernandez, F. J., Fierro, F., Gutierrez, S, Kosalkova, K . Marcos, A. T., Martin, J. F., Velasco, J. (1994). "Expression of Genes and Processing of Enzymes for the Biosynthesis of Penicillins and Cephalosporms". Anton Van Lee. 65 (3): 227–43. doi:10.1007/BF00871951. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ 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.
  12. ^ James, PharmD, Christopher W. (2001 January). "Cross-reactivity of beta-lactam antibiotics". Baylor University Medical Center Proceedings. 14 (1). Dallas, Texas: Baylor University Medical Center: 106–7. PMC 1291320. PMID 16369597. {{cite journal}}: |access-date= requires |url= (help); Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ Kasten, Britta; Reski, Ralf (30 March 1997). "β-lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon esculentum)". Journal of Plant Physiology. 150 (1–2): 137–140. {{cite journal}}: Unknown parameter |link2= ignored (help)
  14. ^ a b c British Pharmacopoeia Commission Secretariat. "Index (BP 2009)" (PDF). Retrieved 26 March 2010. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  15. ^ Cite error: The named reference AMH2006 was invoked but never defined (see the help page).
  16. ^ "Start of World War II." Legacy Publishers. 2 Apr. 2008
  17. ^ Parascandola, John (1980). The History of antibiotics: a symposium. American Institute of the History of Pharmacy No. 5. ISBN 0-931292-08-5.

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