00:01
Now, that’s okay, if you see a polar group
attached. So, for example, an amine group
or maybe a carboxylic acid group, you should
be able to confidently say that it should
have a better spectrum of activity than penicillin
G.
00:12
Now, I’d like to bring us onto the problem
of beta-lactamases.
00:17
Penicillin-resistant bacteria can produce
beta-lactamases which catalyse the hydrolysis
of that beta-lactam bond, thus inactivating
the penicillin. Let us have a look at this
example again.
00:30
This is the general structure of a penicillin
and beta-lactamases act on it to break open
that beta-lactam bond, thus giving us the
amine and the free carboxylic acid. The action
of a beta-lactamase destroys the antibiotic
activity of the penicillin. And what we’ve
seen more recently is the... the expression
perhaps of more beta-lactamases by bacteria
as resistance is gained. This is a real problem
in terms of the efficacy of the antibiotics
that we would want to use.
01:04
So, what are the ways around it? Let’s move
on and discuss this further.
01:10
So, the problem of beta-lactamase-producing
bacteria: how can this be overcome? So, to
start off with it was important to recognise
that beta-lactamases themselves are not very
tolerant to steric hindrance. That is to say
bulky groups near the side chain amide bond
in the sixth position. And this was discovered
with the synthesis of methicillin shown here
in the bottom left hand side. The presence
of those o-methyl groups in the ortho position
adjacent to that amide bond in the sixth position
of the penicillin actually confer on it a
resistance to beta-lactamases. And so, methicillin
resistance was considered to be a benchmark
of bacteria which actually produced a different
isoform of the penicillin-binding protein
through the [Unaware 00:24:38].
02:01
What is interesting to note, however, is that,
if you move those bulky groups, one CH2 group,
away from the amide bond in the sixth position,
you actually create something which goes back
to being beta-lactamase sensitive. This is,
of course, problematic because it means that
that resistance that’s imparted through
the bulky groups only takes place if they’re
very, very close to that amide.
02:24
Another thing to bear in mind, of course,
is that lacking a polar group or an electron-withdrawing
group, is also means that not only is methicillin
a narrow-spectrum antibiotic for Gram-positive
bacteria, but it’s also not orally bio-available.
02:39
So, as I said, methicillin itself is not orally
active due to the absence of electron-withdrawing
groups in the side chain. And it was this
next class of penicillin-based antibiotics
which were designed to combat that.
02:56
As you can see from the structure, they possess
this ring system known, in this case, as an
isoxazolyl ring system characterised by the
presence of the nitrogen and the oxygen next
to each other. This conveys on it a degree
of bulk or steric hindrance which actually
serves to inhibit beta-lactamases, but also
provides or allows it to engage with the penicillin-binding
protein.
03:22
At the same time, the isoxazolyl ring itself
serves as an electron sink pulling electron
density away from that amide in the sixth
position, therefore conveying on it oral bio-availability.
03:35
And so, indeed, you may have actually had
some of these to treat an infection. There
are flucloxacillin, where you have chlorine
and fluorine substituted in the benzene ring
and oxacillin, where you have no substitution
at all.
03:50
As we said, in the absence of having polar
groups such as our NH2 or, for example, carboxylic
acid groups, they also have a very narrow
spectrum of activity and are not particularly
active at all against Gram-negative bacteria.