Now, we come onto to the final lecture in
Module 4. And this relates to beta-lactam
Hopefully, you’ll be able to appreciate,
having gone through a number of functional
groups, some of the structural changes that
we make to these antibiotics in order to improve
their spectrum of activity, their resistance
to beta-lactamases and also, as we will see,
their oral bio-availability.
As you’ll probably be aware, antibiotics
are one of the most-frequently prescribed
medications. They achieve this by selective
toxicity to the pathogen which is a key concept
in antibiotic therapy. And approximately,
half of the world’s sales of antibiotics
are due to the beta-lactam class of antibiotic,
which we’ll be discussing today.
They all work in pretty much the same way,
that is to say, they disrupt bacterial cell
wall synthesis. And they are good examples
of enzyme inhibitors that are irreversible.
Bacterial cell walls offer a selective target
for therapy in the case of bacteria because
normal healthy eukaryotic cells, of course,
do not have cell walls, consisting of a cell
So, let’s touch upon penicillins.
Before I go into the full structure of penicillins,
I’d like you to pay attention to the sub-structure
I’ve shown on the right hand side. This,
you should recognise from Module III, is an
amide. Note, we have a carbonyl-carbon to
which is attached a nitrogen. But, it is a
particular type of amide. It is cyclic. And
cyclic amides are known as lactams. And it
is this beta-lactam, because we have an alpha
and a beta carbon separating the carbonyl
and the nitrogen components, that are the
core component of penicillins.
I’ve shown here, at the bottom right hand
side, the general structure for penicillins.
And these penicillin class were first discovered
in 1929 by Fleming, consisting of a beta-lactam
ring, which is a cyclic amide, fused with
a substituted thiazolidine ring. This is that
five-membered ring that effectively contains
the nitrogen and sulphur at the same time,
What’s interesting is that, whilst it was
discovered in 1929 by Fleming, it was really
the Australian Florey and also the German
chemist Chain that actually led to the drugability
of these molecules. And the problem lay in
the fact that it was difficult to isolate
pure samples of these because of their propensity
for hydrolysis. And, as we’ll see, that
propensity for hydrolysis is what caused some
of the issues with oral bio-availability.
As you can appreciate, where, for example,
we have a beta-lactam group, such as that
shown at the top, we have a very strange ring
structure. We have a very small ring structure
and therefore, the desire for this to open
overcomes in many respects the general lack
of reactivity found in amides.
From a biosynthetic pathway, we’re looking
at the formation of these from cysteine and
valine as the amino acids. And so, when these
are synthesised by a particular penicillium
mould, they are synthesised from cysteine
amino acid and valine amino acid. And you
can see their structures there highlighted
in green and red.
Now, originally, penicillins were produced
by the fermentation of penicillium chrysogenum.
As you can see, they have the general structure
shown in the top right-hand corner. Now, I’m
not necessarily going to go through the full
nomenclature of penicillins because it’s
rather unnecessary. Suffice to say, the majority
of changes which impart a change in pharmacokinetic
profile take place in the sixth position.
The sixth position is marked here as the alpha
position in the beta-lactam ring. And so,
you should pay attention to the changes in
that region as we come along, continue
One of the first penicillins to be obtained
was so-called penicillin G or benzylpenicillin.
And this was actually obtained from culture
when a phenylacetic acid was added to the
medium, thus resulting in the formation of
the benzylamide derivative in that sixth position.
Addition of a phenoxymethylpenicillin actually
resulted in penicillin V, which was one of
the first orally bio-available penicillins.
And this was achieved if phenoxyacetic acid
is added to the medium.
Finally, it wasn’t until 1958 that the first
full synthesis of the precursor to all of
these 6-aminopenicillanic acid, or 6-APA,
was isolated. This, as you can see, is where
we have the free primary amine instead of
that substitution pattern where R = H, in
the case of our structure in the top right
As soon as this penicillanic acid was made
available, an entire raft of thousands of
analogues were made through the partial synthesis,
the semi-synthetic penicillins. For example,
once you have that free amino acid, it’s
possible to create the amide with a wide variety
of different acid chlorides and acid anhydrides.
Note the way the reaction works in this case,
it’s the same as the addition-elimination
reaction we’ve covered in Module III, which
is to say the lone pair on the nitrogen in
the sixth position, as you can see here on
the left hand side, attacks the carbonyl of
an acid chloride, opens up the carbonyl, closes
it, kicks off the chloride.
And so, by this very simple, facile straight
forward reaction, a whole variety of different
penicillanic acid amine... amides could be
synthesised and, of course, then tested for
One of those which you’ll undoubtedly be
familiar with is amoxicillin, which is shown
here, where the R group is that which is directly
attached to an amine and then a hydroxybenzene.
So, let’s have a look at the structural
components of these penicillins, shall we?
Through all of these thousands of analogues
that were synthesised and, obviously, tested
for their antibiotic activity, it was discovered
that the beta-lactam ring, the free carboxylic
acid, the acylamino side chain and the bicyclic
ring were all very useful in terms of activity.
However, only the beta-lactam ring itself
was shown to be an absolute requirement for
antibiotic activity. And this is shown in
the blue circle there.
What this means is, if we lose that beta-lactam
ring, we destroy the antibiotic activity.
Note also the cis-stereochemistry, the cis-relative
stereochemistry, of the hydrogens on the alpha
and beta carbons of that beta-lactam ring
pointing backwards. This is quite important
in terms of its recognition by the target