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Bacteria pose a continual threat of infection, both to humans and to other higher organisms. Thus, when looking for new ways to fight infection, it is often productive to look at how other plants, animals and fungi protect themselves. This is how penicillin was discovered. Through a chance observation in 1928, Alexander Fleming discovered that colonies of Penicillium mold growing in his bacterial cultures were able to stave off infection. With more study, he found that the mold was flooding the culture with a molecule that killed the bacteria, penicillin.

All penicillin's 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 produced.

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.

The spores in Penicillium often contain blue or green pigments which give the colonies on foods and feeds their characteristic colour.


fig: It is the spores in the blue cheese that give the colour to the cheese



The name Penicillium comes from penicillus = brush, and this is based on the brush-like appearance of the fruiting structures.

Penicillium produces brush-like heads. The stalk is called the conidiophore. The conidiophore branches at the tip. At the end of each branchlet is a cluster of spore-producing cells called phialides. A chain of spores is formed from the tip of each phialide. The spore is called a conidium. The spores in Penicillium often contain blue or green pigments which give the colonies on foods and feeds their characteristic colour. As I mentioned before, it is the spores in the blue cheese that give the colour to the cheese. The spores are only a few microns in diameter. I wonder how many millions of spores are eaten in a serving of blue cheese. How would you figure it out? ( hint: need a haemocytometer)


Penicillium Structure

Fig: Penicillin

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 Robert Burns Woodward at Harvard University 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 their 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.


Magic Bullet:

Penicillin and other beta-lactam antibiotics (named for an unusual, highly reactive lactam ring) are very efficient and have few side effects (apart from allergic reactions in some people). This is because the penicillin attacks a process that is unique to bacteria and not found in higher organisms. As an additional advantage, the enzymes attacked by penicillin are found on the outside of the cytoplasmic membrane that surrounds the bacterial cell, so the drugs can attack directly without having to cross this strong barrier

Brusting Bacteria:

When treated with low levels of penicillin, bacterial cells change shape and grow into long filaments. As the dosage is increased, the cell surface loses its integrity, as it puffs, swells, and ultimately ruptures. Penicillin attacks enzymes that build a strong network of carbohydrate and protein chains, called peptidoglycan, that braces the outside of bacterial cells. Bacterial cells are under high osmotic pressure; because they are concentrated with proteins, small molecules and ions are on the inside and the environment is dilute on the outside. Without this bracing corset of peptidoglycan, bacterial cells would rapidly burst under the osmotic pressure.

Blocking Construstion:

( Mechanism of action )

Penicillin is chemically similar to the modular pieces that form the peptidoglycan, and when used as a drug, it blocks the enzymes that connect all the pieces together. As a group, these enzymes are called penicillin-binding proteins. Some assemble long chains of sugars with little peptides sticking out in all directions. Others, like the D-alanyl-D-alanine carboxypeptidase/transpeptidase shown here (PDB entry 3pte), then crosslink these little peptides to form a two-dimensional network that surrounds the cell like a fishing net.

Mechanism of action

Penicillin Biosynthesis

Penicillin Biosynthesis


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 level, nitrogen level, Lysine level, Phosphate level, and oxygen availability 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 on the home front. A War Production Board was founded to monitor job distribution and production. 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 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.

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

Penicillin Resistance:

ptr Of course, bacteria are quick to fight back. Bacteria reproduce very quickly, with dozens of generations every day, so bacterial evolution is very fast. Bacteria have developed many ways to thwart the action of penicillin. Some change the penicillin-binding proteins in subtle ways, so that they still perform their function but do not bind to the drugs. Some develop more effective ways to shield the sensitive enzymes from the drug or methods to pump drugs quickly away from the cell. But the most common method is to create a special enzyme, a beta-lactamase (also called penicillinase) that seeks out the drug and destroys it.

Beta-lactamases, like the one shown on the right (PDB entry 4blm), have a similar serine in their active site pocket. Penicillin also binds to this serine, but is then released in an inactivated form. Other beta-lactamases do the same thing, but use a zinc ion instead of a serine amino acid to inactivate the penicillin.

ptr Many beta-lactamases use the same machinery as used by the penicillin-binding proteins--so similar, in fact, than many researchers believe that the beta-lactamases were actually developed by evolutionary modification of penicillin-binding proteins.

Penicillin Binding Proteins:

The penicillin-binding proteins, (PDB entry 3pte), use a serine amino acid in their reaction, colored purple here. The serine forms a covalent bond with a peptidoglycan chain, then releases it as it forms the crosslink with another part of the peptidoglycan network. Penicillin binds to this serine but does not release it, thus permanently blocking the active site

Beta-lactamases, (PDB entry 4blm), have a similar serine in their active site pocket. Penicillin also binds to this serine, but is then released in an inactivated form. Other beta-lactamases do the same thing, but use a zinc ion instead of a serine amino acid to inactivate the penicillin.






Penicillin Further Classified As:


ptr Beta-lactamase sensitive

ptr benzathine penicillin

ptr benzylpenicillin (penicillin G)

ptr phenoxymethylpenicillin (penicillin V)

ptr procaine penicillin

ptr oxacillin

ptr Penicillinase-resistant penicillins

ptr methicillin

ptr oxacillin

ptr nafcillin

ptr cloxacillin

ptr dicloxacillin

ptr flucloxacillin

ptr β-lactamase-resistant penicillins

ptr temocillin


ptr amoxycillin

ptr ampicillin


ptr co-amoxiclav (amoxicillin+clavulanic acid)


ptr azlocillin

ptr carbenicillin

ptr ticarcillin

ptr mezlocillin

ptr piperacillin

Adverse Effects:

Common adverse drug reactions (>=1% of patients) associated with use of the penicillins include diarrhea, hypersensitivity, nausea, rash, neurotoxicity 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.[18]

Pain and inflammation at the injection site is also common for parenterally administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.

Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin;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. Anaphylaxis will occur in approximately 0.01% of patients. 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.However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins. Recent papers have shown that a 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.