Overview – Cell Wall Synthesis Inhibitors (Antibiotics)

00:01 Welcome to pharmacology by Lecturio.

00:03 I'm Doctor Praveen Shukla and we're going to talk today about antibacterial agents.

00:09 Antibacterial agents fall in several categories.

00:12 We've divided them up here into bacterial cell wall inhibitors, bacterial protein synthesis inhibitors, agents acting against DNA and folic acid, and the anti mycobacterial agents.

00:25 To start off with, let's look at the bacterial cell wall synthesis inhibitors.

00:29 We divide these up into several classes.

00:31 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.

00:48 The first one is n-acetylmuramic acid.

00:51 The second is n-acetylglucosamine.

00:53 We'll call them NAM and NAG, just to make things a little simple.

00:56 Now they get joined together like cars on a train.

00:59 So there's a very long chain of these NAM and NAG particles that make up a train.

01:05 In order to make a wall, we need two trains bound together.

01:09 So what we do is we take two chains, chains of amino acids, and we lash them together.

01:15 Now, right now, when you look at them in the picture here, it's just a loose knot.

01:20 But what we're going to do is we're going to use a thing called a penicillin binding protein.

01:24 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.

01:44 How do we stop the production of this wall? We use something called a β-lactam antibiotic.

01:50 Now, this β-lactam ring binds to the penicillin-binding protein and prevents it from doing its job.

01:57 What ends up happening is you have a wall that isn't being built.

02:02 The β-lactam antibiotic binds to the penicillin-binding protein, and it prevents the cross-linking of NAM and NAG chains to each other.

02:14 Well, what does that do to an existing bacteria? Nothing. The cell wall was already built.

02:19 What really matters, though, is when the cell wall, pardon me,when the cell wants to start replicating itself.

02:26 So as the cell stretches and decides to divide, the dividing cell can't build new cell wall.

02:35 What you end up with is the existing bacteria and something else called a spheroplast.

02:41 Well, what's a spheroplast? Essentially, a spheroplast is a bacteria without a cell wall.

02:46 Now these spheroplasts are essentially useless.

02:49 They can't do what they're supposed to do, which is infect the body.

02:53 So bacteria that attempt to grow and divide in the presence of penicillin end up shedding their cell walls, and they stop dividing.

03:03 The remaining spheroplasts auto catalyze.

03:06 They break down on their own and they die.

03:09 How is it that we get resistance to these antibiotics? There's three major ways.

03:14 First, there's β=lactamase mediated resistance.

03:18 Now what is β-lactamase mediated resistance? β-lactamases are enzymes within the bacteria itself that actually break down that β-lactam ring.

03:27 If you think about it, it's kind of like warfare.

03:30 The mechanism of most types of resistance occurs through β- lactamases.

03:36 They break down the very antibiotic that's supposed to be killing them.

03:40 This will affect many antibiotics that have a β-lactam ring.

03:44 So this includes the penicillins, the cephalosporins, some of the cephamycins and other carbapenems. So what is a β-lactamase? Well you have here a picture of a β-lactamase.

03:57 It's a beautiful illustration.

03:59 You can see how complex a structure this actually is.

04:03 They're also called penicillinases or cephalosporinases.

04:07 But I would just like you to use the term β-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.

04:20 They're usually secreted and may be secreted in response to the presence of an antibiotic.

04:26 So sometimes β-lactamase mediated 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.

04:39 This has become a huge problem now with cephalosporins.

04:42 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.

04:54 This is a new chromosomal-mediated mechanism.

04:57 It's a new threat that we're starting to see.

04:59 We started to see it around 2016 and over the last several years has become more and more prominent.

05:06 We're also seeing now β-lactamase mediated resistance with some of the cephamycins.

05:10 So this is something that we're seeing more and more over time.

05:14 It's going to be more and more important as, as practice goes on.

05:19 Now what do we do about these β-lactamases? Well, specifically with the penicillin based β-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.

05:33 So for example, we will pair clavulanic acid with amoxicillin so that we have a combination of medications that's relatively β-lactamase resistant.

05:44 Sulfur bacteria is another one.

05:46 We put it together with ampicillin or tazobactam.

05:49 We'll put together with piperacillin as combination products.

05:53 And they're often sold as combination products on the market.

05:57 The other way that we develop resistance to the β-lactam antibiotics are penicillin-binding protein-mediated resistance mechanisms.

06:06 So this is actually a lot simpler than it sounds.

06:09 Basically, we have a penicillin-binding protein that is resistant to the effects of the β-lactam.

06:16 Now how does that work? Now if you look here we have a picture of naked DNA from the resistant bacteria.

06:23 That naked DNA actually gets incorporated into the cell.

06:27 The host DNA is now changed.

06:30 Okay. When that host DNA produces a new penicillin binding protein, it's slightly different.

06:37 And it's different enough that it is resistant to the β- lactam but is still able to produce a cell wall.

06:43 So you can actually have transmission of DNA from one bacteria to another that provides the resistance. And you produce new penicillin-binding proteins.

06:54 This gives you a reduced affinity to the new β-lactam antibiotic, or to the old β-lactam antibiotic.

07:00 And that's how these types of resistances spread.

07:03 The third type of resistance is called porin-mediated resistance, and it sounds exactly like it is.

07:11 So porins are basically pores.

07:14 They're water-filled channels.

07:16 Here's a beautiful illustration of a porin.

07:19 Now, a porin is a tubular structure that is seen in the cell walls.

07:23 The antibiotics travel through porins to get inside the bacteria.

07:28 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.

07:37 And we see that actually in Pseudomonas all the time.

07:40 Pseudomonas is very commonly recognized as one of the agents that has porin-mediated resistance.

07:46 Now I'll give you a trick for the exams.

07:48 Porin-mediated Pseudomonas both start with P.

07:51 And this is something that got me through at least one of the questions on my exam.

07:55 So try to remember Porin Pseudomonas makes things a little bit easier to remember.