Welcome to pharmacology by Lecturio.
I'm Dr. Praveen Shukla, and we're going
to talk today about antibacterial agents.
antibacterial agents fall in several categories.
We've divided them up here
into bacterial cell wall inhibitors,
bacterial protein synthesis inhibitors, agents
that are acting against DNA and folic acid,
and the anti-mycobacterial agents.
To start off with, let's look at the
bacterial cell wall synthesis inhibitors.
We divide these up into several classes.
We have the oldest of the
group, which are the penicillins,
cephalosporins, the penems
and other miscellaneous agents.
How is it that we build a cell wall?
Well, cell wall synthesis in the
bacteria starts with two major proteins.
The first one is N-acetylmuramic acid.
The second is N-acetylglucosamine.
We'll call them NAM and NAG
just to make things a little simple.
Now they get joined together like cars on a train.
So there's a very long chain of these
NAM and NAG particles that make up a train.
In order to make a wall, we
need two trains bound together.
So what we do is we take two chains, chains
of amino acids, and we lashed them together.
Now right now when you look at them
in the picture here, it's just a loose knot.
But what we're going to do is we're going to
use a thing called a penicillin-binding protein.
Now this protein comes along,
cleaves off two of the end units,
binds them together tightly, and
keeps on doing that over and over again,
until you have a very long set
of two trains hooked together
to make a strong cell wall for the bacteria.
How do we stop the production of this wall?
We use something called a beta-lactam antibiotic.
Now this beta-lactam ring binds to the penicillin
binding protein and prevents it from doing its job.
What ends up happening is you
have a wall that isn't being built.
The beta lactam antibiotic binds
to the penicillin binding protein,
and it prevents the cross linking of
NAM and NAG chains to each other.
Well, what does that do to an existing bacteria?
Nothing, the cell wall was already built.
What really matters though, is when
the cell wall, pardon me, when the cell
wants to start replicating itself.
So as the cell stretches and decides to divide,
the dividing cell can't build new cell wall.
What you end up with is the existing
bacteria and something else called a spheroplast.
Well, what's a spheroplast?
Essentially a spheroplast is
a bacteria without a cell wall.
Now these spheroplasts are essentially
useless, they can't do what they're supposed to do,
which is infect the body.
So bacteria that attempt to grow
and divide in the presence of penicillin,
end up shedding their cell
walls and they stop dividing.
The remaining spheroplasts auto catalyze,
they break down on their own and they die.
How is it that we get
resistance to these antibiotics?
There's three major ways.
First, there's beta-lactamase-mediated resistance.
Now, what is beta lactamase resistance?
beta lactamase is our enzymes within the bacteria
itself that actually break down that beta-lactam ring.
If you think about it, it's kind of like warfare.
The mechanism of most types of
resistance occurs through beta lactamases.
They break down the very antibiotic
that's supposed to be killing them.
This will affect many antibiotics
that have a beta-lactam ring.
So this includes the penicillins, cephalosporins,
some of the cephamycins, and other carbapenems.
So what is a beta-lactamase?
Well, you have here a picture of a beta-lactamase.
It's a beautiful illustration, you can see
how complex a structure this actually is.
They're also called penicillinases
But I would just like you to use
the term beta-lactamase, because
it really reminds us of
where these drugs are acting.
Now they're produced by gram-positive organisms,
but they also can be produced
by gram-negative organisms.
They're usually secreted and may be secreted
in response to the presence of an antibiotic.
So sometimes beta lactamase
resistance isn't really obvious
until you actually expose
the organism to an antibiotic.
And then all of a sudden you realize, oh my
gosh, this, this particular organism is resistant.
This has become a huge
problem now with cephalosporins.
And of course, you all probably know
already that we use cephalosporins
much more than we have been using penicillins.
Now, sometimes the resistance with
cephalosporins is a little bit different.
This is a new chromosomal- mediated mechanism.
It's a new threat that we're starting to see.
We started seeing at around
2016, and over the last several years
has become more and more prominent.
We're also seeing now beta-lactamase
resistant with some of the cephamycins.
So this is something that we're
seeing more and more over time,
it's going to be more and more
important as practice goes on.
Now, what do we do about these beta-lactamases?
Well, specifically with the
penicillin based beta-lactamases,
we can counter it with certain
types of inhibitors of these enzymes.
One of them and probably the most
commonly known is clavulanic acid.
So, for example, we will pair
clavulanic acid with amoxicillin
so that we have a combination of medications
that's relatively beta-lactamases resistant.
Sulfabactam is another one,
we put it together with ampicillin,
or Tazobactam, we'll put together
with piperacillin as combination products,
And they're often sold as
combination products on the market.
The other way that we develop
resistance to the beta lactamase antibiotics
are penicillin-binding protein
mediated resistance mechanisms.
So this is actually a lot simpler than it sounds.
Basically, we have a penicillin binding protein
that is resistant to the effects of the beta lactamase.
Now, how does that work?
Now, if you look, here, we have a picture
of naked DNA from the resistant bacteria.
That naked DNA actually
gets incorporated into the cell.
The host DNA is now changed.
Okay, when that host DNA produces a new
penicillin binding protein, it's slightly different.
And it's different enough that it
is resistant to the beta lactamase,
but is still able to produce a cell wall.
So you can actually have transmission
of DNA from one bacteria to another
that provides the resistance, and you
produce new penicillin binding proteins.
This gives you a reduced affinity to the new beta-lactam
antibiotic or to the old beta-lactam antibiotic.
And that's how these types of resistances spread.
The third type of resistance is
called porin-mediated resistance.
And it sounds exactly like it is.
So porins are basically pores.
They're water-filled channels.
Here's a beautiful illustration of a porin.
Now a porin is a tubular structure
that is seen in the cell walls.
The antibiotics travel through
porins to get inside the bacteria.
But if you have a bacteria, for example,
that adapts and makes fewer porins,
you'll have less ability
for the antibiotic to get in.
And we see that actually in
Pseudomonas all the time.
Pseudomonas is very commonly recognized as
one of the agents that has porin-mediated resistance.
Now I'll give you a trick for the exams.
Porin-mediated, Pseudomonas both start with P.
And this is something that got me through
at least one of the questions on my exams.
So try to remember, porin, Pseudomonas
makes things a little bit easier to remember.