Penicillin

‡ 1928: Alexander Fleming noticed that a mould (penicillium notatum) produced a compound that inhibits bacterial growth. ‡ 1940: Florey and Chain showed that an injection of extract cured infections in mice and later in humans. ‡ 1945: Fleming, Florey and Chain were awarded a Nobel Prize for Medicine.

CH CH HC CH C CH

CH2 C O

NH HC C O

S HC N HC C O C

CH3 CH3

OH

Penicillin-G

Penicillin works by inhibiting an enzyme involved in the building of bacterial cell walls.

The mould extract was broken down if taken by mouth and effective only against a limited range of bacteria. In the 1950s it was shown that penicillin-G could be broken down to give 6-amino penicinillic acid from which a range of semisynthetic penicillins could be made.

CH CH HC CH C CH

CH2 C O

NH HC C O

S HC N HC C O C

CH3 CH3

OH

H2N HC C O

S HC N HC C C

CH3 CH3

OH

6-APA

O

O C R Cl H2N HC C O HC N

S C HC C O

CH3 CH3

OH

O C R

NH HC C O

S HC N HC C O C

CH3 CH3

OH

Unfortunately penicillins are fragile

What is the bond angle here ? What does it ³want´ to be ? ow can it get there ?

O C R

NH CH C O

S HC NH OH O HC C C

CH3 CH3

OH

Bacteria that have the enzyme -lactamase can hydrolyse the strained amide group. These are resistant. Why does this resistance spread? Suggest 2 ways of overcoming this resistance.

1) Make a penicillin that does not fit into the active site of -lactamase : Methacillin 2) Inhibit lactamase by mixing the active penicillin with Clavulanic acid

C C C C C C C C C C C C C C S C

C

3

C

3

C
2C

2

C C C

C

C C

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