Diphtheria

=__**Disease/Drug of interest** : __ Diphtheria/ Penicillin=

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Diphtheria is a toxin-mediated disease that is caused by a particular strain of Corynebacterium diphtheriae. When Corynebacterium diphtheriae is lysogenize by a certain virus with tox gene, it expresses the gene and releases toxin which caused Diphtheria in human. Diphtheria is not known for causing death among various other diseases; however, it was so well examined that the study model became the base to study polio, influenza and much other infection diseases[1]. =====

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The disease was first recognized as diphtheria by Bretonneau in 1826. According to Australian statistic, diphtheria was almost an exclusive disease among the younger children in the 1860s. Diphtheria can infect several different organs and body parts, including the anterior of nose, pharynx and tonsils, larynx and skin [2]. Pharynx and tonsils remain the most common sites of diphtheria infection. The symptoms are myalgia, sore throat, anorexia and low-grade fever. If it is left untreated, a bluish-white membrane may form and create various sizes of small patches covering the tonsils. When a higher dose of toxin is absorbed, the patient may even develop marked edema of the submandibular areas and the anterior neck along with lymphadenopathy. Eventually, striking pallor, severe prostration and rapid pulse, stupor, and coma can develop in some patients, who may even die within 6 to 10 days [3]. =====

__ Target Information** : ** __

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Penicillin destroys disease-causing bacterias by interrupting their catalytic pathway of the transpeptidase, which is used to make the cross-linkage in cell walls. The specific transpeptidase that penicillin targeted at is called the penicillin-binding proteins (PBPs). PBPs are common constituents of a cell wall and cytosol in bacteria. Because PBPs include a wide range of proteins, the molecular weight of PBPs in a single strain of bacteria can range from 40,000 to 91,000 [2]. =====

[[image:http://prodata.swmed.edu/wenlin/pdb_survey2/index.cgi/pdb_pic/3a3d/A/290-296 height="350"]]
Figure 2: Crystal representation of Penicillin-Binding Protein 4 (dacb) from Haemophilus Influenzae [11].

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The function of PBPs is to complete the final stage of cell wall synthesis in bacteria. During bacterial division, it must leave spaces temporarily in between its cell wall so that it can grow and later separated from their mother cells. The spaces will then be filled with newly synthesized peptidoglycan. To form a stable peptidoglycan, cross-linkage is used to connect a series of sugar polymers (NAM-NAG) [4]. ===== Figure 3: The mechanism of penicillin blocking the catalysis activity of transpeptidase to synthesis trans-peptide [10]. PBP involves in the making of cross-linking in bacteria cell walls, but when it is blocked by penicillin with a beta-lactam ring, it can be permanently inhibited.

=__**Drug Information**** : **__=
 * Schematic figure of drug ** :

Figure 4: the 2D molecular structure of penicillin G [5]

The drug should be delivered intravenously[5]
 * Formula ** : C 16 H 18 N 2 O 4 S [5]
 * Molecular weight ** : 334.39 g/mol [5]
 * CAS Number ** : 61-33-6 [5]
 * Delivery method ** :

The side effects include: Black or hairy tongue; exaggerated reflexes; mild diarrhea; nausea or vomiting; pain, swelling, or redness at the injection site; twitching[3]
 * Side effects ** :

Penicillin is a generic antibacterial drug that is often addressed as Amoxicillin, Ampicillin, bacampicillin, etc. [6].
 * Other names ** :

Penicillin G is one of the products of Pfizer [4]
 * Maker or company ** :

In 1945, Andrew Jackson Moyer patented the methods for mass production of penicillin [7].
 * Is it patented ** ?


 * Clinical Trials Info ** :

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Because penicillin can be used to treat many different diseases, many clinical trials were performed; however, the very first clinical trial happened in February 1941. Fletcher, Florey, and Chain decided that delivering the drug intravenously was the most efficient method. They administered 200 mg and then 300 mg penicillin intravenously every three hours. All patients reported to improve; however, the supply of penicillin exhausted before their patient could be saved. The total dose given within the five day period was only 220,000 units which are too small of an amount as they realized later. There was no reported toxic effect during the five days continuous administration of penicillin [10]. Penicillin was first derived from a particular strain of Penicillium notatum [2]. =====

__** Origin ** : __

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Alexander Fleming, the professor of bacteriology at St. Mary’s Hospital in London, was the first person to discover the antibiotic characteristic of penicillin during World War II. He found that the “mold juice” of a rare strain of Penicillium notatum was capable of killing various harmful bacterias, including streptococcus, meningococcus and the diphtheria bacillus. Despite their major discovery, Fleming and his colleagues were unsuccessful in isolating penicillin as a stable antibiotic drug. It was not until 1993, Howard Florey, Ernst Chain and their peers at the Sir William Dunn School of Pathology at Oxford University brought this idea into a practical life-saving drug [7]. =====


 * Alternatives to this drug ** :

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Patients who are allergic to penicillin can receive similar antibiotics such as cephalosporin or carbapenem. Patient with unknown statistics should go through a series of examination including penicillin skin test before giving any penicillin or carbapenem. If the skin test is positive, beta-lactams should be avoided. On the other hand, patients with negative skin test result can be challenged with penicillin, cephalosporin, or carbapenem [9]. =====

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Despite its powerful curing effect, penicillin is so overused that some strains of bacteria start to develop resistance. Many more penicillin derivatives were invented to battle this problem, at the same time, medical professors become more cautious when prescribing penicillin. =====


 * References/ ****External links:**

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1. Center for Disease Control. Immunology and Preventive Diseases: Diphtheria. [|__https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/dip.pdf__] (accessed Feb 03, 2017). =====

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2. Spratt B.G. Properties of the penicillin-binding proteins of Escherichia coli K12, J. Eur J Biochem.1977 Jan, 72,(2), 341–52. =====

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3. Pfizerpen. Product Information. [|__https://www.drugs.com/sfx/penicillin-g-potassium-side-effects.html__] ( accessed Feb 03, 2017) =====

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4. Pirt, S.J.; Righelato, R.C. Effect of Growth Rate on the Synthesis of Penicillin by Penicillium chrysogenum in Batch and Chemostat Cultures. Appl Environ Microbiol. 1967November, 15,(6), 1284-1290. =====

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8. ACS Chemistry for Life. Discovery and Development of Penicillin. [|__https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html#alexander-fleming-penicillin__] (accessed Feb 03, 2017). =====