00:00
So, that’s brilliant. But, there are problems.
00:04
The problems stem from the original penicillin
that we look at: benzylpenicillin. It was
acid sensitive. It was not active over a wide
range of bacteria and it was also sensitive
to these additional enzymes produced by certain
resistant kinds of bacteria called beta-lactamase.
00:22
And what medicinal chemists have set out to
do is to try and overcome these disadvantages
through making a wide variety of penicillin
analogues actually using rational chemistry
to try and improve upon the pharmacokinetic
properties and pharmacodynamic properties
of these. So, let’s have a look at those
problems and solutions in a little bit more
detail.
00:46
We discussed actually part of this earlier
on in the module about the problem of acid
sensitivity. So, this is just going to be
a brief recap in this case.
00:55
In the presence of catalytic amounts of acid,
intramolecular hydrolysis of the beta-lactam
group can occur. I will not go through the
full method and full mechanism since we have
covered that earlier on in this module. But,
just to reiterate that where you’ve got
this nucleophilic oxygen as part of the sixth-position
amide, this can kick in, open up the beta-lactam
ring, thus splitting up the beta-lactam four-membered
ring system and rendering our penicillin now
completely inactive. And this is the problem
with oral bio-availability of penicillin G
or benzylpenicillin.
01:33
A way around this was, of course, to actually
add an electron-withdrawing group in the R
position. And this is shown here. This is
one of the earlier orally bio-available penicillins,
penicillin V, where in this scenario, the
R group attached to that carbonyl as part
of the amide in the sixth position is electron
withdrawing.
01:54
As you can see from this arrow, what this
means is it pulls electron density away from
the carbonyl-carbon making it less nucleophilic,
thus producing its propensity to then attack
the carbonyl of the beta-lactam ring. The
electron density ultimately is on the carb-...
02:11
is reduced on the carbonyl and therefore,
it can be given orally. And it should be stressed
that, if you were to see the structure of
an unknown penicillin and you should see an
electron-withdrawing group directly attached
to that sixth position, you should be able
to say confidently that it’d most likely
be orally bio-available.
02:32
The other problem we have is narrow spectrum
of activity. Benzylpenicillin and phenoxymethyl
penicillin, penicillin V, are useful mainly
against Gram-positive bacteria. And this prompted
the development of ampicillin and amoxicillin,
the general structure for which is shown here.
02:49
As you can see, we have a couple of slight
variations. Instead of having an oxygen in
the case of penicillin V neighbouring our
carbonyl group on the amide, we now have an
NH2 group attached. In the case of amoxicillin,
we also have a, in the fourth position of
that benzene ring, a hydroxyl substitution.
03:10
And the reason that this seems to work is
by virtue of the fact that polar groups in
that position, next to the amide on the sixth
position of the bicyclic ring system of the
penicillin seem to impart broader spectrum
of activity. And this was determined experimentally
rather than with any particular rationale
in mind.
03:34
Amoxicillin has better activity against Gram-negative
bacteria than the other penicillins because
it’s related to the ability of the penicillin
to cross the cell wall.
03:44
If I cast your minds back to where we looked
at the general structures of the cell walls
between Gram-positive and Gram-negative, this
makes some sense. In the case of Gram-positive
bacteria, the cell wall is effectively exposed
and so, therefore, is the enzyme peptide...
03:59
penicillin-binding protein. If we look on
the Gram-negative side of things, the peptidoglycan
was hidden between a layer of lipopolysaccharide.
And so, in this particular scenario, it was
determined experimentally that incorporating
a polar group in that sixth position actually
improved the ability to penetrate that lipopolysaccharide
layer through the porin substructure. It’s
thought that penicillins, which have got those
polar groups attached, can more easily pass
through porins in the outer membrane, thus
accessing the peptidoglycan layer underneath.