Penicillin

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.

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

Penicillium 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 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). Return to Penicillium 

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

Bursting 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 Construction 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.

Penicillin Resistance 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.

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.

PDB entry 3pte

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.

PDB entry 4blm