Penicillin (1).ppt
Transcript of Penicillin (1).ppt
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Penicillin
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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 fightinfection, 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.
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The spores in
Penicilliumoften contain
blue or green
pigments which
give the
colonies on
foods and
feeds their
characteristic
colour. It is the
spores in the
blue cheesethat give the
colour to the
cheese.
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Penicillium
The name Penicillium comes from penicillus = brush, and this is based on
the brush-like appearance of the fruiting structures
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Penicillium produces brush-like heads. The stalk iscalled the conidiophore. The conidiophore branches atthe tip. At the end of each branchlet is a cluster ofspore-producing cells called phialides. A chain ofspores is formed from the tip of each phialide. The
spore is called a conidium. The spores in Penicilliumoften contain blue or green pigments which give thecolonies on foods and feeds their characteristiccolour. As I mentioned before, it is the spores in the bluecheese that give the colour to the cheese. The spores
are only a few microns in diameter. I wonder how manymillions of spores are eaten in a serving of blue cheese.How would you figure it out? ( hint: need ahaemocytometer). Return to Penicillium
http://www.uoguelph.ca/~gbarron/MISCELLANEOUS/penicill.htmhttp://www.uoguelph.ca/~gbarron/MISCELLANEOUS/penicill.htmhttp://www.uoguelph.ca/~gbarron/MISCELLANEOUS/penicill.htmhttp://www.uoguelph.ca/~gbarron/MISCELLANEOUS/penicill.htm -
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Magic Bullet
Penicillin and other beta-lactam antibiotics(named for an unusual, highly reactive lactamring) are very efficient and have few side effects(apart from allergic reactions in some people).
This is because the penicillin attacks a processthat is unique to bacteria and not found in higherorganisms. As an additional advantage, theenzymes attacked by penicillin are found on theoutside of the cytoplasmic membrane that
surrounds the bacterial cell, so the drugs canattack directly without having to cross this strongbarrier
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Bursting Bacteria
When treated with low levels of penicillin, bacterial cellschange shape and grow into long filaments. As thedosage is increased, the cell surface loses its integrity,as it puffs, swells, and ultimately ruptures. Penicillinattacks enzymes that build a strong network ofcarbohydrate and protein chains, called peptidoglycan,that braces the outside of bacterial cells. Bacterial cellsare under high osmotic pressure; because they areconcentrated with proteins, small molecules and ions are
on the inside and the environment is dilute on theoutside. Without this bracing corset of peptidoglycan,bacterial cells would rapidly burst under the osmoticpressure.
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Blocking Construction
Penicillin is chemically similar to the modular pieces thatform the peptidoglycan, and when used as a drug, itblocks the enzymes that connect all the pieces together.
As a group, these enzymes are called penicillin-bindingproteins. Some assemble long chains of sugars with littlepeptides sticking out in all directions. Others, like the D-alanyl-D-alanine carboxypeptidase/transpeptidaseshown here (PDB entry 3pte), then crosslink these little
peptides to form a two-dimensional network thatsurrounds the cell like a fishing net.
http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=3PTEhttp://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=3PTE -
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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 tothwart the action of penicillin. Some change the penicillin-binding proteins in subtle ways, so that they still perform theirfunction but do not bind to the drugs. Some develop moreeffective ways to shield the sensitive enzymes from the drug ormethods to pump drugs quickly away from the cell. But themost common method is to create a special enzyme, a beta-lactamase (also called penicillinase) that seeks out the drugand destroys it.
Beta-lactamases, like the one shown on the right (PDB entry4blm), have a similar serine in their active site pocket. Penicillinalso binds to this serine, but is then released in an inactivatedform. Other beta-lactamases do the same thing, but use a zinc
ion instead of a serine amino acid to inactivate the penicillin.
http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=4BLMhttp://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=4BLM -
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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.
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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 apeptidoglycan chain, then releases it as it
forms the crosslink with another part of the
peptidoglycan network. Penicillin binds tothis serine but does not release it, thus
permanently blocking the active site.
http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=3PTEhttp://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=3PTE -
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PDB entry 3pte
http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=3PTEhttp://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=3PTE -
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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. Otherbeta-lactamases do the same thing, but
use a zinc ion instead of a serine amino
acid to inactivate the penicillin.
http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=4BLMhttp://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=4BLM -
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PDB entry 4blm
http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=4BLMhttp://www.rcsb.org/pdb/cgi/explore.cgi?pid=26461020379874&pdbId=4BLM