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