Penicillin (1).ppt

7/30/2019 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.


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PDB entry 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.


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PDB entry 4blm

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Penicillin (1).ppt