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.
 S CH3
CH CH2 NH
CH HC C
C C HC CH3
N HC
HC CH O C
CH C OH
O

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 semi-
synthetic penicillins could be made.
 S CH3
CH CH2 NH
CH HC C
C C HC CH3
N HC
HC CH O C
CH C OH
O

S CH3
H2N
HC C
HC CH3
N HC
C

C OH
O

6-APA O
 O
S CH3
H2N
C HC
HC C
R Cl CH3
N HC
C

C OH
O

O S CH3
NH
C HC C
HC CH3

R N HC
C
C OH
O

O
Unfortunately penicillins are fragile

O S CH3
NH
C HC C
HC CH3

R N HC
C
C OH
O
O

What is the bond angle here ?

What does it “want” to be ?
How can it get there ?
 O S CH3
NH
C HC C
CH CH3

R NH HC
C

O OH C OH

Bacteria that have the enzyme β-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 H
O
penicillin that CH
C
H
S
CH3
C H
does not fit HC
NH
HC
HC C
CH3

into the C C
N HC

active site of CH C
C O O
C
O
β-lactamase : O C
H
HO

Methacillin H
H

2) Inhibit β-
lactamase by H2C HC
O CH2 OH

mixing the C CH

active penicillin C N
HC
O
with Clavulanic C
O
acid HO