Structural Biochemistry/Enzyme/Reversible Inhibitors/Competitive Inhibitor/Penicillin

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Introduction[edit | edit source]

Penicillin is an antibiotic agent that was earliest discovered and used widely. This antibiotic agent was derived from the Penicillium mold. Since antibiotics released by fungi and bacteria act as a natural substances that inhibits other organisms, it is then a chemical warfare on a microscopic scale. Penicillian is used to treat variety of infections and micro-organism.

History[edit | edit source]

Alexander Fleming

Penicillin was first noticed in 1896 by Ernest Duchesne, a French medical student. Then in 1928, it was re-discovered by Alexander Fleming, a bacteriologist, who worked the London's St. Mary's Hospital. During Fleming's work at the hospital, he noticed a Staphylococcus plate culture that was contaminated by a blue-green mold. At the same time, the colonies of bacteria that were next to the mold were dissolved. With much curiosity, Fleming began to grow the mold in a pure culture; as a result, he found that it formed a substance that killed a number of disease-causing bacteria. From the observations and experiments, Fleming named the substance penicillin, and Fleming published the results in 1929.

In 1938, Howard Florey, Ernst Chain and Norman Heatley continued the research of penicillin at Oxford University. During that period of time, the three scientists and their staff developed methods for growing, extracting, and purifying penicillin to prove its value as a drug.

Then during the World War II (1939 - 1945) period, penicillin became very useful. In 1941, the research and production of penicillin moved to the United States. It was to protect the progress and production of penicillin from bombings in England. More and more work began on the growing of mold to make penicillin in large quantities for thousands of soldiers. When the amount of people dying began to grow, the interest in penicillin also grew in laboratories, universities, and drug companies. Scientist at that time knew that they were in a race against death, and since this infection was able to kill a wounded soldier through a small wound.

Penicillin as an Inhibitor[edit | edit source]

Penicillin kills bacteria by interfering with the ability to synthesize cell wall. The bacteria lengthen, but cannot divide. Eventually the weak cell wall ruptures.

Penicillin irreversibly blocks bacterial cell wall synthesis by inhibiting the formation of peptidoglycan cross-links. Penicillin covalently binds to the enzyme transpeptidase that links the peptidoglycan molecules in bacteria, it inhibits the molecule so that it cannot react any further and cell wall cannot be further synthesized. The cell wall of the bacterium is weakened even further because the build-up of peptidoglycan precursors triggers bacterial cell wall hydrolysis and autolysins, and destroys pre-existing peptidoglycan. Penicillin makes a great inhibitor because of its four membered beta lactam ring, which makes it especially reactive. Penicillin acts as a suicide inhibitor by binding with the transpeptidase enzyme it inactivates itself.

Gram positive bacteria are the most sensitive and susceptible to penicillin because Gram positive bacteria only have murein (peptidoglycan) layer. Gram negative bacteria are usually more resistant to penicillin because they have multiple membrane layers, which allows them to still retain a cell wall even though they have lost their murein layer to penicillin. Penicillin can be used to treat Gram positive bacteria such as streptococcus pneumoniae, staphylococcus aureus, enterococcus, clostridium tetani, and listeria monocytogenes. Penicillin cannot be used to treat gram negative bacteria such as neisseria gonorrhoeae, neisseria meningitidis, pseudomonas, legionella, escherichia coli, helicobacter pylori (stomach ucler), borrelia burgdorfeli (lyme disease), treponema pallidium (syphilus), and chlamydia trachomatis.

File:Penicillin2.jpg File:Penicillin1.jpg

Some bacteria have developed resistance to beta-lactams. These bacteria contain beta-lactamases, a broad class of enzymes with a serine residue that cleaves the reactive beta lactam ring through an acyl-enzyme intermediate. Augmentin, a drug that contains both a beta-lactam (typically amoxicillin) and clavulanic acid (a beta-lactamase inhibitor), is often prescribed to overcome drug resistant strains. Clavulanic acid works by competitive inhibition.

Types of penicillin[edit | edit source]

Benzylpenicillin[edit | edit source]


Benzylpenicillin, commonly known as penicillin G, is known as the gold standard penicillin. It is given by a method of non-oral administration (parentally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, tissue concentrations of penicillin G can be achieved in larger levels than is possible with other types of penicillin, like phenoxymethylpenicillin. These higher concentrations become increased antibacterial levels or activities.

Uses for benzylpenicillin include:

  • Cellulitis
  • Bacterial endocarditis
  • Gonorrhea
  • Meningitis
  • aspiration pneumonia, lung abscess
  • Community-acquired pneumonia
  • Syphilis
  • Septicemia in children

Phenoxymethylpenicillin/penicillin V[edit | edit source]

Phenoxymethylpenicillin is the orally active form of penicillin. It is less frequently used than benzylpenicillin, and is mostly used in conditions when high tissue is not required. However, it is the first choice when it comes to treating odontogenic (relating to the teeth) infections.

Procaine[edit | edit source]

Procaine benzylpenicillin (rINN), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. It is absorbed into the circulation by means of deep intramuscular injection. It is used when prolonged low concentrations of benzylpenicilin are needed, and mostly used in veterinary environments as well as dental offices. The common trade name for procaine is Novocain which is typically administered to patients at the dentist office before undergoing minor surgery. It is metabolized in the blood plasma by an enzyme called pseudocholinesterase. Procaine replaced cocaine as a local anesthetic due to the severe side effects caused by cocaine.

Benzathine[edit | edit source]

Benzathine benzylpenicillin (rINN), also known as benzathine penicillin, is absorbed into the circulation slowly by intramuscular injection like procaine penicillin, but then it is hydrolysed to benzylpenicillin in vivo. It is the number one drug choice when prolonged low concentrations are required and appropriate. It allows for antibiotic action to be prolonged over two to four weeks following just one dose.

Other examples of penicillin include amoxcillin, ampicillin, methicillin, oxacillin, and temocillin. Amoxcillin and ampicillin are the most common penicillins that are prescribed by doctors because they are used to treat common infections such as throat infections.

Side effects[edit | edit source]

Just like any other drug on the market, penicillin may cause unpleasant side effects for patients taking it. Some of the side effects are commonly found on patients using penicillin are: diarrhea, hypersensitivity, nausea, rash, neurotoxicity urticaria, seizures. Pain and inflammation at the injection site is also common for the partenterally administered penicillin types. 3% to 10% of the population is allergic to penicillin. Usually when allergic to one type of penicillin, you are allergic to the entire family of penicillin antibiotics. The problems mentioned about diarrhea and nausea tend to go away for most patients after a few doses of the drug. If further symptoms occur, however, the drug should not be taken anymore. Physicians say that any drug that interferes with cellular growth, in this case the cell wall can have severe side effects on a large population of patients. The most common side effects caused by penicillin are:

  1. diarrhea that is watery or bloody
  2. fever, chills, body aches, flu symptoms
  3. easy bruising or bleeding, unusual weakness
  4. urinating less than usual or not at all
  5. severe skin rash, itching, or peeling
  6. agitation, confusion, unusual thoughts or behavior
  7. seizure (black-out or convulsions)
  8. nausea, vomiting, stomach pain
  9. vaginal itching or discharge
  10. headache
  11. swollen, black, or "hairy" tongue
  12. thrush (white patches or inside your mouth or throat)

Penicillin allergy[edit | edit source]

Penicillin and related antibiotics can cause an allergic reaction in some people. Although, not all adverse reactions to penicillin are a sign of an allergic reaction. True allergic reactions involve the immune system and can cause signs and symptoms that range from an annoying rash to a life-threatening reaction or anaphylaxis with low blood pressure and trouble breathing. β-lactam antibiotic can end up causing allergic reactions to about 10% of the patients. However, even though penicillin are very commonly reported in allergy cases, but less than 20% of those reports are truly allergic. But it is definitely a drug that can cause major, severe reactions.

It isn't clear why some people develop penicillin allergy while others don't. Treating an allergic reaction may require taking medications or emergency care in serious cases.

Penicillin Resistance[edit | edit source]

Penicillin has been a widely used antibiotic for years. Although there has been evidence of new bacterium evolving to become resistant the penicillin. Penicillin is used to stop the bacteria from building their cell walls called peptidoglycan. The penicillin resistant bacterium have been shown to be creating dipeptide bridges in their peptidoglycan. Researchers have found that bacteria that form dipeptide bonds in their peptidoglycan use a protein called MurM which helps in building dipeptide bridges within the peptidoglycan. Researchers are trying to use the information to begin targeting MurM to help bring penicillin back to the forefront of antibiotics. Also to note is that when patients that are taken penicillin to treat bacteria that it is necessary to take penicillin for the full duration of the required time because although the penicillin may kill most of the bacteria if not taken for the full duration can allow for a few bacterium to live, the most fit for survival to live and repopulate in the patient therefore creating a more penicillin resistant bacteria.

Sources[edit | edit source]

Berg, Jeremy M. John L. Tymoczko. Lubert Stryer. Biochemistry Sixth Edition. W.H. Freeman and Company. New York, 2007.

Structure of Penicillin: Biology 103 - Microbes:

"Characterization of tRNA-dependent Peptide Bond Formation by MurM in the Synthesis of Streptococcus pneumoniae Peptidoglycan." J. Biol. Chem. Vol. 283, Issue 10, pp 6402-6417, March 7, 2008