Transcript Penicillin - Stephen F. Austin State University

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. 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 Dalanyl-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 penicillinbinding 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 betalactamase (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 penicillinbinding proteins--so similar, in fact, than
many researchers believe that the betalactamases were actually developed by
evolutionary modification of penicillinbinding 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