Address of Some biological Research institutes
1. Institute of Life Sciences,Nalco Square, Chandrasekharpur,Bhubaneswar-751 023
Phone: 91-0674-2301900, 2300137, 2301460, 2301476, 2300129
Fax: (0674) 2300728,Email : bbmishra@ils.res.in
2. Agharkar Research Institute, Gopal Ganesh Agarkar Road,Pune – 411004,Maharashtra, India.
Phones : +91-20-25654357, +91-20-25653680,Fax : +91-020-25651542,
E-mail : director@aripune.org ,URL : www.aripune.org,Applications : jobs@aripune.org
3.Bhabha Atomic Research Centre,Trombay,Mumbai - 400 085,INDIA
Tel:+91-22-25505050 / 25505010 ,Fax:+91-22-25505151 / 25519613
webmaster@barc.gov.in
4. Center for DNA Fingerprinting and Diagnostics [CDFD] ,ECIL Road, Nacharam ,Hyderabad-500 076, INDIA
Tel:+91-40-27151344 ,Fax:+91-40-27155610
5.Director, IGCAR,dir@igcar.gov.in,Phone: 044-27480240,Office of Director, IGCAR
dirsec@igcar.gov.in,hone: 044-27480267,Fax: 044-27480060
6. INSTITUTE OF BIORESOURCES AND SUSTAINABLE DEVELOPMENT( IBSD)
(an autonomous institute under Deptartment of Biotechnology, Ministry of Science & Technology, Govt. of India),TAKYELPAT, IMPHAL, MANIPUR- 795001 (INDIA)
PHONE: 91-385-2446121/ 2446122, FAX: 91-385-2446120
E-MAIL : ibsd_imp@sancharnet.in
7. Institute of Genomics and Integrative Biology,Near Jubilee Hall, Mall Road, Delhi-110 007
Ph. No. 91-011-27666156/157, 27667602, 27667439
Fax:91-011-27667471
8. National Centre for Biological Sciences,Tata Institute of Fundamental Research
GKVK, Bellary Road,Bangalore 560065, India,Phone: 91 80 23636421/ 429
Fax: 91 80 23636662.
9. National Centre for Cell Sciences (NCCS) ,NCCS Complex, University of Pune Campus, Ganeshkhind, Pune 411007, Maharashtra, India ,Phone: +91-20-25708000 ,Fax:+91-20-25692259
10. National Institute for Plant Genome Research,Aruna Asaf Ali Marg, P.O. Box No. 10531
New Delhi - 110 067 ,Email : administration@nipgr.res.in , nipgr@nipgr.res.in
Ph. No. : 91-11-30942824, 26735169
91-11-26741612, 14, 17 Ext. 143
Direct - 91-11-26735143, Fax: 91-11-26741658
Friday, June 13, 2008
Some Biotech Companies in India
Biotech Companies in India
Strand Genomics - Bioinformatics software design and development
Ocimum BioSolutions - Bioinformatics software modules and training
Manvish Infotech - Specializes in embedded systems, bioinformatics and content development
BrainWave - Contract based research in bioinformatics and genome studies
Bioinformatics Institute of India - Non-profit research and development centre
Bigtec - Bioinformatics and medical informatics research
Avestha Gengraine - Bioinformatics research and development
AUKBC - Research in communications, networking, mathematics and bioinformatics
Center for DNA Fingerprinting & Diagnostics - DNA, fingerprinting, molecular diagnostics & bioinformatics
Bioinformatics Centre, Madurai Kamaraj University - Research in genetic engineering, molecular biology and biophysics
Bioinformatics Center - Biotechnolgy related information provider
A.V.Thomas Biotechnolgy - Commercial plant tissue culture laboratory
Amersham Biosciences - Focuses on disease research, and drug development
AstraZeneca - Research on infectious diseases and drugs
Avestha Gengraine - Bioinformatics research and development
Bangalore Bio - Resource on biotech companies, institutes and policies
Bangalore Genei - Manufacturer of reagents and equipment for DNA research
Bigtec - Bioinformatics and medical informatics research
Bio-Instruments - Distributor of biotechnology and agri-research instruments
BioSoft - Application of biotechnology in acqaculture management
Biotech India - Molecular biology, immunology and cell biology research products
Biotech Support Services - Resource on biotechnology industry & services
Biotron Healthcare - Supplier of biotechnology instruments
Esscee Biotech - Synthetic DNA and RNA manufacturer
Genotypic Technologies - Nucleic acids and cDNA library construction services
Greenearth Biotechnologies - Tissue culture research and plants supplier
Growmore Biotech - Commercial plant tissue culture
Harrisons Malayalam - Plant tissue culture
Strand Genomics - Bioinformatics software design and development
Ocimum BioSolutions - Bioinformatics software modules and training
Manvish Infotech - Specializes in embedded systems, bioinformatics and content development
BrainWave - Contract based research in bioinformatics and genome studies
Bioinformatics Institute of India - Non-profit research and development centre
Bigtec - Bioinformatics and medical informatics research
Avestha Gengraine - Bioinformatics research and development
AUKBC - Research in communications, networking, mathematics and bioinformatics
Center for DNA Fingerprinting & Diagnostics - DNA, fingerprinting, molecular diagnostics & bioinformatics
Bioinformatics Centre, Madurai Kamaraj University - Research in genetic engineering, molecular biology and biophysics
Bioinformatics Center - Biotechnolgy related information provider
A.V.Thomas Biotechnolgy - Commercial plant tissue culture laboratory
Amersham Biosciences - Focuses on disease research, and drug development
AstraZeneca - Research on infectious diseases and drugs
Avestha Gengraine - Bioinformatics research and development
Bangalore Bio - Resource on biotech companies, institutes and policies
Bangalore Genei - Manufacturer of reagents and equipment for DNA research
Bigtec - Bioinformatics and medical informatics research
Bio-Instruments - Distributor of biotechnology and agri-research instruments
BioSoft - Application of biotechnology in acqaculture management
Biotech India - Molecular biology, immunology and cell biology research products
Biotech Support Services - Resource on biotechnology industry & services
Biotron Healthcare - Supplier of biotechnology instruments
Esscee Biotech - Synthetic DNA and RNA manufacturer
Genotypic Technologies - Nucleic acids and cDNA library construction services
Greenearth Biotechnologies - Tissue culture research and plants supplier
Growmore Biotech - Commercial plant tissue culture
Harrisons Malayalam - Plant tissue culture
Saturday, June 7, 2008
Penicillin
Penicillin
Penicillin (sometimes abbreviated PCN) is a group of beta-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. “Penicillin” is also the informal name of a specific member of the penicillin group Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain.
The discovery of penicillin is usually attributed to Scottish scientist Sir Alexander Fleming in 1928 and the development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey.
However, several others had earlier noted the antibacterial effects of Penicillium such as Ernest Duchesne, who documented it in his 1897 paper; however it was not accepted by the Institut Pasteur because of his young age. Furthermore, in March 2000, doctors of the San Juan de Dios Hospital in San Jose (Costa Rica) published manuscripts belonging to the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887-1944). The manuscripts explained Picado's experiences between 1915 and 1927 about the inhibitory actions of the fungi of genera Penic. Clorito Picado had reported his discovery to the Paris Academy of Sciences in Paris, yet did not patent it, even though his investigation had started years before Fleming's.
Fleming recounted later that the date of his breakthrough was on the morning of Tuesday, September 28, 1928. At his laboratory in the basement of St. Mary's Hospital (Imperial College) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould Staphylococcus plate culture. Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mould and discovered that 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, but, in particular, noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae). After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to get someone to purify it until 1940.
In 1939, Astralian scientist Howard Florey, Baron Florey and a team of researchers (Ernst Boris Chain, A. D. 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 due to insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved its harmlessness and effect on mice.[4]
A moldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest-quality penicillin after a world-wide search.[5]
Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On 1942-03-14, John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.[6][7]
Penicillin was being mass-produced in 1944
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. 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. Penicillins are actively secreted, and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times, it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused.[8]
This was not a satisfactory solution, however; so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.[8] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[9]
The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s. A team of Oxford research scientists led by Australian Howard Florey, Baron Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass-producing the drug. Chemist John 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. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work, and, after WWII, Australia was the first country to make the drug available for civilian use. Penicillin has since become the most widely-used antibiotic to date, and is still used for many Gram-positive bacterial infections.
Developments from penicillin
The narrow 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 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.
The line of true penicillins was the antipseudomonal penicillins, such as 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, have this at the center of their structures.[10]
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 auto lysins, 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.
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.
Benzathine benzylpenicillin
Benzathine benzylpenicillin (rINN), also known as benzathine penicillin, is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin L-A.
Specific indications for benzathine pencillin include:[9]
Prophylaxis of rheumatic fever
Early or latent syphilis
Benzylpenicillin (penicillin G)
Penicillin G
Systematic (IUPAC) name
4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-((phenylacetyl)amino)- (2S-(2α,5α,6β))-
Identifiers
Chemical data
Formula
C16H18N2O4S
Mol. mass
334.4 g/mol
Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route of administration (not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.
Specific indications for benzylpenicillin include:[9]
Cellulitis
Bacterial endocarditis
Gonorrhea
Meningitis
aspiration pneumonia, lung abscess
Community-acquired pneumonia
Syphilis
Septicaemia in children
Phenoxymethylpenicillin (penicillin V)
Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is appropriate only in conditions where high tissue concentrations are not required.
Specific indications for phenoxymethylpenicillin include:[9]
Infections caused by Streptococcus pyogenes
Tonsillitis
Pharyngitis
Skin infections
Prophylaxis of rheumatic fever
Moderate-to-severe gingivitis (with metronidazole)
Penicillin V is the first choice in the treatment of odontogenic infections.
Procaine benzylpenicillin
Procaine benzylpenicillin (rINN), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required.
This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings.
It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R.[11] As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels.[12]
Respiratory tract infections where compliance with oral treatment is unlikely
Cellulitis, erysipelas
Procaine penicillin is also used as an adjunct in the treatment of anthrax.
Semi-synthetic penicillins
Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability to beta-lactamase activity, and increase the spectrum of action.
Narrow spectrum penicillinase-resistant penicillins
This group was developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillin. Penicillin is rampantly used for curing infections and to prevent growth of harmful mold.
Methicillin discontinued (not used clinically)
Dicloxacillin
Flucloxacillin
Oxacillin
Nafcillin
Cloxacillin
Narrow spectrum β-lactamase-resistant penicillins
This molecule has a spectrum directed toward Gram-negative bacteria without activity on Pseudomonas aeruginosa or Acinetobacter spp. with remarkable resistance to any type of β-lactamase.
Temocillin
Moderate spectrum penicillins
This group was developed to increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability.
Amoxicillin
Ampicillin
And the prodrugs of ampicillin that are converted in the body to ampicillin:
Hetacillin, not used now.
Bacampicillin
Pivampicillin
Extended Spectrum Penicillins
This group was developed to increase efficacy against Gram-negative organisms. Some members of this group also display activity against Pseudomonas aeruginosa. These are divided into carboxypencillins and ureidopenicillins.
Carboxypencillins
Carbenicillin
Ticarcillin
Ureidopenicillins
Mezlocillin
Piperacillin
Azlocillin
Penicillins with beta-lactamase inhibitors
Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not, in general, in itself, increase the spectrum of the partner penicillin.
Amoxicillin/clavulanic acid
Ampicillin/sulbactam
Ticarcillin/clavulanic acid
Piperacillin/tazobactam
Other Penicillins
Metampicillin
Broadcillin
Epicillin
Ampicillin benzathine
Talampicillin
Combipenix
Ampicillinoic acid
N-(N'-Methylasparaginyl)amoxicillin
Aspoxicillin
N-Propionylampicillin
Lenampicillin
Sulacillin
Adverse effects
Adverse drug reactions
Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and/or pseudomembranous colitis.[9]
Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.
Allergy/hypersensitivity
Although penicillin is still the most commonly-reported allergy, less than 20% of all patients that believe that they have a penicillin allergy are truly allergic to penicillin;[13] nevertheless, penicillin is still the most common cause of severe allergic drug reactions.
Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent.[14] Anaphylaxis will occur in approximately 0.01% of patients.[9] It has previously been accepted that there was up to a 10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems, due to the sharing of the β-lactam ring.[15][16] However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins. Recent papers have shown that major feature in determining immunological reactions is the similarity of the side chain of first generation cephalosporins to penicillins, rather than the β-lactam structure that they share.
Penicillin Production
The production of penicillin is an area that requires scientists and engineers to work together to achieve the most efficient way of producing large amounts of penicillin.
It must be understood that penicillin is a secondary metabolite of fungus Penicillium, which means the fungus will not produce the antibiotics while it is growing, but will produce penicillin when it feels threatened. There are also other factors that inhibit penicillin production. One of these factors is the synthesis pathway of penicillin:
α-ketoglutarate + AcCoA -> homocitrate -> L-α-aminoadipic acid -> L-Lysine + β-lactam
It turns out that the by-product L-Lysine will inhibit the production of homocitrate, so the presence of exogenous lysine should be avoided in the penicillin production.
The penicillium cells are grown using a technique called fed-batch culture; this way the cells are constantly subject to stress and will produce plenty of penicillin. The carbon sources that are available are also important: Glucose will inhibit penicillin, whereas lactose does not. The pH level, nitrogen level, Lysine level, Phosphate level, and oxygen availability of the batches must be controlled automatically.
Other area of biotechnology such as directed evolution can also be applied to mutate the strains into producing a much larger number of penicillin. These directed-evolution techniques include error-prone PCR, DNA shuffling, ITCHY, and strand over-lap PCR.
References
1. ^ Kendall F. Haven, Marvels of Science (Libraries Unlimited, 1994) p182
2. ^ Fleming A. (1929). "On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzæ.". Br J Exp Pathol 10 (31): 226–36.
3. ^ Brown, Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN 0-7509-3152-3.
4. ^ Drews, Jürgen (March 2000). "Drug Discovery: A Historical Perspective". Science 287 (5460): 1960 - 1964. Retrieved on 2007-11-17.
5. ^ Mary Bellis. The History of Penicillin. Inventors. About.com. Retrieved on 2007-10-30.
6. ^ Saxon, W.. "Anne Miller, 90, first patient who was saved by penicillin", The New York Times, 1999-06-09.
7. ^ Krauss K, editor (1999). Yale-New Haven Hospital Annual Report (PDF). Yale-New Haven Hospital.
8. ^ a b Silverthorn, DU. (2004). Human physiology: an integrated approach.. Upper Saddle River (NJ): Pearson Education. ISBN 0-8053-5957-5.
9. ^ a b c d e f g (2006) in Rossi S, editor: Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3.
10. ^ James, PharmD, Christopher W.; Cheryle Gurk-Turner, RPh (January 2001). "Cross-reactivity of beta-lactam antibiotics". Baylor University Medical Center Proceedings 14 (1): 106-107. Dallas, Texas: Baylor University Medical Center. Retrieved on 2007-11-17.
11. ^ (2005) "Inadvertent use of Bicillin C-R to treat syphilis infection--Los Angeles, California, 1999-2004". MMWR Morb. Mortal. Wkly. Rep. 54 (9): 217-9. PMID 15758893.
12. ^ United States Food & Drug Administration. "FDA Strengthens Labels of Two Specific Types of Antibiotics to Ensure Proper Use." Published December 1, 2004. Last accessed June 18, 2007.
13. ^ Salkind AR, Cuddy PG, Foxworth JW (2001). "Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy". JAMA 285 (19): 2498–2505.
14. ^ Solensky R (2003). "Hypersensitivity reactions to beta-lactam antibiotics". Clinical reviews in allergy & immunology 24 (3): 201–20. PMID 12721392.
15. ^ Dash CH (1975). "Penicillin allergy and the cephalosporins". J. Antimicrob. Chemother. 1 (3 Suppl): 107–18. PMID 1201975.
16. ^ Gruchalla RS, Pirmohamed M (2006). "Clinical practice. Antibiotic allergy". N. Engl. J. Med. 354 (6): 601-9. doi:10.1056/NEJMcp043986. PMID 16467547.
17. ^ Pichichero ME (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients" (PDF). The Journal of family practice 55 (2): 106–12. PMID 16451776.
18. ^ Pichichero ME (2007). "Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift". Diagn. Microbiol. Infect. Dis. 57 (3 Suppl): 13S–18S. doi:10.1016/j.diagmicrobio.2006.12.004. PMID 17349459.
19. ^ Antunez C, Blanca-Lopez N, Torres MJ, et al (2006). "Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins". J. Allergy Clin. Immunol. 117 (2): 404–10. doi:10.1016/j.jaci.2005.10.032. PMID 16461141.
Penicillin (sometimes abbreviated PCN) is a group of beta-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. “Penicillin” is also the informal name of a specific member of the penicillin group Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain.
The discovery of penicillin is usually attributed to Scottish scientist Sir Alexander Fleming in 1928 and the development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey.
However, several others had earlier noted the antibacterial effects of Penicillium such as Ernest Duchesne, who documented it in his 1897 paper; however it was not accepted by the Institut Pasteur because of his young age. Furthermore, in March 2000, doctors of the San Juan de Dios Hospital in San Jose (Costa Rica) published manuscripts belonging to the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887-1944). The manuscripts explained Picado's experiences between 1915 and 1927 about the inhibitory actions of the fungi of genera Penic. Clorito Picado had reported his discovery to the Paris Academy of Sciences in Paris, yet did not patent it, even though his investigation had started years before Fleming's.
Fleming recounted later that the date of his breakthrough was on the morning of Tuesday, September 28, 1928. At his laboratory in the basement of St. Mary's Hospital (Imperial College) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould Staphylococcus plate culture. Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mould and discovered that 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, but, in particular, noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae). After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to get someone to purify it until 1940.
In 1939, Astralian scientist Howard Florey, Baron Florey and a team of researchers (Ernst Boris Chain, A. D. 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 due to insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved its harmlessness and effect on mice.[4]
A moldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest-quality penicillin after a world-wide search.[5]
Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On 1942-03-14, John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.[6][7]
Penicillin was being mass-produced in 1944
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. 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. Penicillins are actively secreted, and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times, it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused.[8]
This was not a satisfactory solution, however; so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.[8] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[9]
The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s. A team of Oxford research scientists led by Australian Howard Florey, Baron Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass-producing the drug. Chemist John 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. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work, and, after WWII, Australia was the first country to make the drug available for civilian use. Penicillin has since become the most widely-used antibiotic to date, and is still used for many Gram-positive bacterial infections.
Developments from penicillin
The narrow 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 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.
The line of true penicillins was the antipseudomonal penicillins, such as 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, have this at the center of their structures.[10]
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 auto lysins, 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.
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.
Benzathine benzylpenicillin
Benzathine benzylpenicillin (rINN), also known as benzathine penicillin, is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin L-A.
Specific indications for benzathine pencillin include:[9]
Prophylaxis of rheumatic fever
Early or latent syphilis
Benzylpenicillin (penicillin G)
Penicillin G
Systematic (IUPAC) name
4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-((phenylacetyl)amino)- (2S-(2α,5α,6β))-
Identifiers
Chemical data
Formula
C16H18N2O4S
Mol. mass
334.4 g/mol
Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route of administration (not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.
Specific indications for benzylpenicillin include:[9]
Cellulitis
Bacterial endocarditis
Gonorrhea
Meningitis
aspiration pneumonia, lung abscess
Community-acquired pneumonia
Syphilis
Septicaemia in children
Phenoxymethylpenicillin (penicillin V)
Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is appropriate only in conditions where high tissue concentrations are not required.
Specific indications for phenoxymethylpenicillin include:[9]
Infections caused by Streptococcus pyogenes
Tonsillitis
Pharyngitis
Skin infections
Prophylaxis of rheumatic fever
Moderate-to-severe gingivitis (with metronidazole)
Penicillin V is the first choice in the treatment of odontogenic infections.
Procaine benzylpenicillin
Procaine benzylpenicillin (rINN), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required.
This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings.
It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R.[11] As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels.[12]
Respiratory tract infections where compliance with oral treatment is unlikely
Cellulitis, erysipelas
Procaine penicillin is also used as an adjunct in the treatment of anthrax.
Semi-synthetic penicillins
Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability to beta-lactamase activity, and increase the spectrum of action.
Narrow spectrum penicillinase-resistant penicillins
This group was developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillin. Penicillin is rampantly used for curing infections and to prevent growth of harmful mold.
Methicillin discontinued (not used clinically)
Dicloxacillin
Flucloxacillin
Oxacillin
Nafcillin
Cloxacillin
Narrow spectrum β-lactamase-resistant penicillins
This molecule has a spectrum directed toward Gram-negative bacteria without activity on Pseudomonas aeruginosa or Acinetobacter spp. with remarkable resistance to any type of β-lactamase.
Temocillin
Moderate spectrum penicillins
This group was developed to increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability.
Amoxicillin
Ampicillin
And the prodrugs of ampicillin that are converted in the body to ampicillin:
Hetacillin, not used now.
Bacampicillin
Pivampicillin
Extended Spectrum Penicillins
This group was developed to increase efficacy against Gram-negative organisms. Some members of this group also display activity against Pseudomonas aeruginosa. These are divided into carboxypencillins and ureidopenicillins.
Carboxypencillins
Carbenicillin
Ticarcillin
Ureidopenicillins
Mezlocillin
Piperacillin
Azlocillin
Penicillins with beta-lactamase inhibitors
Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not, in general, in itself, increase the spectrum of the partner penicillin.
Amoxicillin/clavulanic acid
Ampicillin/sulbactam
Ticarcillin/clavulanic acid
Piperacillin/tazobactam
Other Penicillins
Metampicillin
Broadcillin
Epicillin
Ampicillin benzathine
Talampicillin
Combipenix
Ampicillinoic acid
N-(N'-Methylasparaginyl)amoxicillin
Aspoxicillin
N-Propionylampicillin
Lenampicillin
Sulacillin
Adverse effects
Adverse drug reactions
Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and/or pseudomembranous colitis.[9]
Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.
Allergy/hypersensitivity
Although penicillin is still the most commonly-reported allergy, less than 20% of all patients that believe that they have a penicillin allergy are truly allergic to penicillin;[13] nevertheless, penicillin is still the most common cause of severe allergic drug reactions.
Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent.[14] Anaphylaxis will occur in approximately 0.01% of patients.[9] It has previously been accepted that there was up to a 10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems, due to the sharing of the β-lactam ring.[15][16] However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins. Recent papers have shown that major feature in determining immunological reactions is the similarity of the side chain of first generation cephalosporins to penicillins, rather than the β-lactam structure that they share.
Penicillin Production
The production of penicillin is an area that requires scientists and engineers to work together to achieve the most efficient way of producing large amounts of penicillin.
It must be understood that penicillin is a secondary metabolite of fungus Penicillium, which means the fungus will not produce the antibiotics while it is growing, but will produce penicillin when it feels threatened. There are also other factors that inhibit penicillin production. One of these factors is the synthesis pathway of penicillin:
α-ketoglutarate + AcCoA -> homocitrate -> L-α-aminoadipic acid -> L-Lysine + β-lactam
It turns out that the by-product L-Lysine will inhibit the production of homocitrate, so the presence of exogenous lysine should be avoided in the penicillin production.
The penicillium cells are grown using a technique called fed-batch culture; this way the cells are constantly subject to stress and will produce plenty of penicillin. The carbon sources that are available are also important: Glucose will inhibit penicillin, whereas lactose does not. The pH level, nitrogen level, Lysine level, Phosphate level, and oxygen availability of the batches must be controlled automatically.
Other area of biotechnology such as directed evolution can also be applied to mutate the strains into producing a much larger number of penicillin. These directed-evolution techniques include error-prone PCR, DNA shuffling, ITCHY, and strand over-lap PCR.
References
1. ^ Kendall F. Haven, Marvels of Science (Libraries Unlimited, 1994) p182
2. ^ Fleming A. (1929). "On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzæ.". Br J Exp Pathol 10 (31): 226–36.
3. ^ Brown, Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN 0-7509-3152-3.
4. ^ Drews, Jürgen (March 2000). "Drug Discovery: A Historical Perspective". Science 287 (5460): 1960 - 1964. Retrieved on 2007-11-17.
5. ^ Mary Bellis. The History of Penicillin. Inventors. About.com. Retrieved on 2007-10-30.
6. ^ Saxon, W.. "Anne Miller, 90, first patient who was saved by penicillin", The New York Times, 1999-06-09.
7. ^ Krauss K, editor (1999). Yale-New Haven Hospital Annual Report (PDF). Yale-New Haven Hospital.
8. ^ a b Silverthorn, DU. (2004). Human physiology: an integrated approach.. Upper Saddle River (NJ): Pearson Education. ISBN 0-8053-5957-5.
9. ^ a b c d e f g (2006) in Rossi S, editor: Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3.
10. ^ James, PharmD, Christopher W.; Cheryle Gurk-Turner, RPh (January 2001). "Cross-reactivity of beta-lactam antibiotics". Baylor University Medical Center Proceedings 14 (1): 106-107. Dallas, Texas: Baylor University Medical Center. Retrieved on 2007-11-17.
11. ^ (2005) "Inadvertent use of Bicillin C-R to treat syphilis infection--Los Angeles, California, 1999-2004". MMWR Morb. Mortal. Wkly. Rep. 54 (9): 217-9. PMID 15758893.
12. ^ United States Food & Drug Administration. "FDA Strengthens Labels of Two Specific Types of Antibiotics to Ensure Proper Use." Published December 1, 2004. Last accessed June 18, 2007.
13. ^ Salkind AR, Cuddy PG, Foxworth JW (2001). "Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy". JAMA 285 (19): 2498–2505.
14. ^ Solensky R (2003). "Hypersensitivity reactions to beta-lactam antibiotics". Clinical reviews in allergy & immunology 24 (3): 201–20. PMID 12721392.
15. ^ Dash CH (1975). "Penicillin allergy and the cephalosporins". J. Antimicrob. Chemother. 1 (3 Suppl): 107–18. PMID 1201975.
16. ^ Gruchalla RS, Pirmohamed M (2006). "Clinical practice. Antibiotic allergy". N. Engl. J. Med. 354 (6): 601-9. doi:10.1056/NEJMcp043986. PMID 16467547.
17. ^ Pichichero ME (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients" (PDF). The Journal of family practice 55 (2): 106–12. PMID 16451776.
18. ^ Pichichero ME (2007). "Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift". Diagn. Microbiol. Infect. Dis. 57 (3 Suppl): 13S–18S. doi:10.1016/j.diagmicrobio.2006.12.004. PMID 17349459.
19. ^ Antunez C, Blanca-Lopez N, Torres MJ, et al (2006). "Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins". J. Allergy Clin. Immunol. 117 (2): 404–10. doi:10.1016/j.jaci.2005.10.032. PMID 16461141.
திரு . அப்துல் கலாம்
Dr.Abdul Kalam.A.P.J.
Dr. Avul Pakir Jainulabhudin Adbul Kalam, the twelfth President of India, is rightfully termed as the father of India's missile technology. He was born to parents
Jainulabdeen Marakayar and Ashiamma on 15th October,1931, at Dhanushkodi in Rameshwaram district, TamilNadu. Dr. Kalam as an eminent Aeronautical Engineer,
contributed for the development of India’s first Satellite launch vehicle SLV-3 and the missiles like the Trishul, Agni, Pritvi etc.
He did his secondary education at Schwartz High School in Ramanathapuram, B.Sc. at St. Joseph's College(1950),Tiruchi, and DMIT in Aeronautical Engineering at the
MIT, Madras during 1954-57. After passing out as a graduate aeronautical engineer, Kalam joined Hindustan Aeronautics Limited (HAL), Bangalore as a trainee and
later joined as a technical assistant in the Directorate of Technical Development and
Production of the Ministry of Defence.
In the 1960's Kalam joined the Vikram Sarabhai Space Centre at Thumba in
Kerala. He played a major role in the centre's evolution to a key hub of space researchin India, helping to develop the country's first indigenous satellite-launch vehicle.
During 1963-82, he served the ISRO in various capacities. In 1982, he rejoined
DRDO as Director, and conceived the Integrated Guided Missile Development
Programme (IGMDP) for five indigenous missiles. Dr. A.P.J. Abdul Kalam has
established an Advanced Technology Research Centre, called 'Research Centre
Imarat' to undertake development in futuristic missile technology areas. He also
served as the Principal Scientific Adviser to the Defence minister and later the
Government of India. After retiring from the post Dr. Kalam joined Annamalai
University till he became the President in January 2002.
He is a member of Indian National Academy of Sciences, Astronautical Society of
India and many other professional bodies. Dr. APJ abdul Kalam has been awarded
Padma Bhushan in 1981, Padma Vibhushan in 1990 and India's Highest civilian
Award 'The Bharat Ratna' in 1997. Other prestigious awards include Dr.Biren Roy
Space Award, Om Prakash Basin Award for Science and Technology, National Nehru
Award, Arya Bhatta Award etc. Dr. Kalam was conferred with the degree of Doctor
of Science (D.Sc. Honoris-causa) by twenty eight universities.
Dr. Kalam, a bachelor is a connoisseur of classical Carnatic music. He plays veena in
his leisure. He writes poetry in Tamil, his mother tongue. Seventeen of his poems
were translated into English and published in 1994 as a book entitled 'My Journey'.
He reads the Quran and the Bhagavad Gita with equal devotion. He is also the Author
of the books 'India 2020 : A vision for the New Millennium'(1998 with YS Rajan),
'Wings of Fire : an Autobiography' and 'Ignited Minds – unleashing the power within
India'.
Totally dedicated to the nation, Dr. Abdul Kalam's vision is to transform India into a developed nation by the year 2020 through hard work and perseverance. He holds a
first world dream for the third world nation.
Dr. Avul Pakir Jainulabhudin Adbul Kalam, the twelfth President of India, is rightfully termed as the father of India's missile technology. He was born to parents
Jainulabdeen Marakayar and Ashiamma on 15th October,1931, at Dhanushkodi in Rameshwaram district, TamilNadu. Dr. Kalam as an eminent Aeronautical Engineer,
contributed for the development of India’s first Satellite launch vehicle SLV-3 and the missiles like the Trishul, Agni, Pritvi etc.
He did his secondary education at Schwartz High School in Ramanathapuram, B.Sc. at St. Joseph's College(1950),Tiruchi, and DMIT in Aeronautical Engineering at the
MIT, Madras during 1954-57. After passing out as a graduate aeronautical engineer, Kalam joined Hindustan Aeronautics Limited (HAL), Bangalore as a trainee and
later joined as a technical assistant in the Directorate of Technical Development and
Production of the Ministry of Defence.
In the 1960's Kalam joined the Vikram Sarabhai Space Centre at Thumba in
Kerala. He played a major role in the centre's evolution to a key hub of space researchin India, helping to develop the country's first indigenous satellite-launch vehicle.
During 1963-82, he served the ISRO in various capacities. In 1982, he rejoined
DRDO as Director, and conceived the Integrated Guided Missile Development
Programme (IGMDP) for five indigenous missiles. Dr. A.P.J. Abdul Kalam has
established an Advanced Technology Research Centre, called 'Research Centre
Imarat' to undertake development in futuristic missile technology areas. He also
served as the Principal Scientific Adviser to the Defence minister and later the
Government of India. After retiring from the post Dr. Kalam joined Annamalai
University till he became the President in January 2002.
He is a member of Indian National Academy of Sciences, Astronautical Society of
India and many other professional bodies. Dr. APJ abdul Kalam has been awarded
Padma Bhushan in 1981, Padma Vibhushan in 1990 and India's Highest civilian
Award 'The Bharat Ratna' in 1997. Other prestigious awards include Dr.Biren Roy
Space Award, Om Prakash Basin Award for Science and Technology, National Nehru
Award, Arya Bhatta Award etc. Dr. Kalam was conferred with the degree of Doctor
of Science (D.Sc. Honoris-causa) by twenty eight universities.
Dr. Kalam, a bachelor is a connoisseur of classical Carnatic music. He plays veena in
his leisure. He writes poetry in Tamil, his mother tongue. Seventeen of his poems
were translated into English and published in 1994 as a book entitled 'My Journey'.
He reads the Quran and the Bhagavad Gita with equal devotion. He is also the Author
of the books 'India 2020 : A vision for the New Millennium'(1998 with YS Rajan),
'Wings of Fire : an Autobiography' and 'Ignited Minds – unleashing the power within
India'.
Totally dedicated to the nation, Dr. Abdul Kalam's vision is to transform India into a developed nation by the year 2020 through hard work and perseverance. He holds a
first world dream for the third world nation.
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