Download Penicillin

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
CH2
C
C
CH
O
CH3
S
NH
HC
HC
C
C
N
HC
C
O
O
Penicillin-G
CH3
OH
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
CH2
NH
C
C
CH
O
HC
HC
C
N
C
CH
CH3
S
HC
C
O
O
CH3
S
H2N
HC
HC
C
C
N
CH3
HC
C
O
6-APA
CH3
O
OH
OH
O
C
R
CH3
S
H2N
HC
HC
Cl
C
N
C
CH3
HC
OH
C
O
O
O
NH
C
CH3
S
HC
HC
R
C
C
N
CH3
HC
C
O
O
OH
Unfortunately penicillins are fragile
O
NH
C
CH3
S
HC
HC
C
N
R
CH3
HC
C
C
O
O
What is the bond angle here ?
What does it “want” to be ?
How can it get there ?
OH
O
NH
C
CH
R
HC
C
NH
C
O
CH3
S
CH3
HC
OH
C
OH
O
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
penicillin that
does not fit
into the
active site of
β-lactamase :
Methacillin
2) Inhibit βlactamase by
mixing the
active penicillin
with Clavulanic
acid
H
O
C
H
CH
C
H
NH
HC
C
HC
CH3
HC
C
CH
CH3
S
C
N
HC
C
C
O
C
O
H
O
C
HO
H
H
CH2
O
H2C
HC
C
C
CH
N
HC
O
C
HO
O
OH
O