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Overview – Cell Wall Synthesis Inhibitors (Antibiotics)
Welcome to pharmacology by Lecturio. 00: I'm Doctor Praveen Shukla and we're going to talk today about antibacterial agents. 00: Antibacterial agents fall in several categories. 00: 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: To start off with, let's look at the bacterial cell wall synthesis inhibitors. 00: We divide these up into several classes. 00: 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: The first one is n-acetylmuramic acid. 00: The second is n-acetylglucosamine. 00: We'll call them NAM and NAG, just to make things a little simple. 00: Now they get joined together like cars on a train. 00: So there's a very long chain of these NAM and NAG particles that make up a train. 01: In order to make a wall, we need two trains bound together. 01:
So what we do is we take two chains, chains of amino acids, and we lash them together. 01: Now, right now, when you look at them in the picture here, it's just a loose knot. 01: But what we're going to do is we're going to use a thing called a penicillin binding protein. 01: 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: How do we stop the production of this wall? We use something called a β-lactam antibiotic. 01: Now, this β-lactam ring binds to the penicillin-binding protein and prevents it from doing its job. 01: What ends up happening is you have a wall that isn't being built. 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: Well, what does that do to an existing bacteria? Nothing. The cell wall was already built. 02: What really matters, though, is when the cell wall, pardon me,when the cell wants to start replicating itself. 02: So as the cell stretches and decides to divide, the dividing cell can't build new cell wall. 02: What you end up with is the existing bacteria and something else called a spheroplast. 02: Well, what's a spheroplast? Essentially, a spheroplast is a bacteria without a cell wall. 02:
You can see how complex a structure this actually is. 04: They're also called penicillinases or cephalosporinases. 04: 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: They're usually secreted and may be secreted in response to the presence of an antibiotic. 04: 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: This has become a huge problem now with cephalosporins. 04: 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: This is a new chromosomal-mediated mechanism. 04: It's a new threat that we're starting to see. 04: We started to see it around 2016 and over the last several years has become more and more prominent. 05: We're also seeing now β-lactamase mediated resistance with some of the cephamycins. 05: So this is something that we're seeing more and more over time.
It's going to be more and more important as, as practice goes on. 05: 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: 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: Sulfur bacteria is another one. 05: We put it together with ampicillin or tazobactam. 05: We'll put together with piperacillin as combination products. 05: And they're often sold as combination products on the market. 05: The other way that we develop resistance to the β-lactam antibiotics are penicillin-binding protein-mediated resistance mechanisms. 06: So this is actually a lot simpler than it sounds. 06: Basically, we have a penicillin-binding protein that is resistant to the effects of the β-lactam. 06: Now how does that work? Now if you look here we have a picture of naked DNA from the resistant bacteria. 06: That naked DNA actually gets incorporated into the cell. 06:
Pseudomonas is very commonly recognized as one of the agents that has porin-mediated resistance. 07: Now I'll give you a trick for the exams. 07: Porin-mediated Pseudomonas both start with P. 07: And this is something that got me through at least one of the questions on my exam. 07: So try to remember Porin Pseudomonas makes things a little bit easier to remember. Cephalosporins: 00: Next we have the cephalosporins. 00: The cephalosporins are divided into generations. 00: Let's start with the first generation cephalosporins. 00: The most commonly used is Cefazolin. 00: Cefazolin has excellent coverage against gram positive organisms. 00:
And if you think about it, it's an excellent antibiotic to use in surgical infections. 00: Now, if you have a skin infection, Cefazolin is probably your go to drug. 00: However, cefazolin does not have much effectiveness against gram-negative bacteria. 00: So for example, if you had a urinary tract infection, cefazolin is not going to be very intelligent empiric antibiotic choice. 00: Okay, I had said before that the first generation cephalosporins had excellent gram-positive coverage, but not so great gram-negative coverage. 00: As we move down in the generations, you'll start to see that the higher generation medications have better and better coverage for gram-negative organisms. 01: Now, those gram-negative organisms can be seen in respiratory tract infections. 01: We often think of as a second-generation cephalosporins as being respiratory drugs. 01: Why is that? Because for upper respiratory infections have a lot of gram-positive organisms and some gram-negative organisms. 01: For example, cefuroxime works against gram-negative bacteria quite nicely, and it works very well against Haemophilus influenza. 01: So if we have a person who has either a strep infection or Haemophilus infection, but we don't know, will often use cefuroxime. 01: Now, the nice thing about cefuroxime and these drugs is that they also have a little bit of anaerobic activity. 01:
What's a zwitterion? A zwitterion is an ion or a drug that has two different charges on the same molecule. 03: Normally, we think of molecules as either being positively charged or negatively charged, A zwitterion has a positive charge on one end and the negative charge on another. 03: Okay, let's move on. 03: So a fourth generation cephalosporin like cefapime is more resistant to beta lactamase producing organisms. 03: Enterobacter is a particularly difficult infection to treat. 03: We often see this in very sick patients who are in the intensive care unit or on the ward. 03: So, let's say a person comes in. 03: You suspect that they have a beta-lactamase based infection. 03: Cefepime is a really good choice in this particular type of patient. 03: Now we move on to fifth generation cephalosporins. 03: It includes drugs like ceftaroline. 03: Now, I want to make a mention that not everyone accepts the whole nomenclature behind fifth generation cephalosporins. 03: There are some people who just say that all fifth generations are unclassified. 04:
I'll leave that debate alone for a moment. 04: Now take a look at this structure. It's a very complicated structure. 04: So you can see, that these fifth generation cephalosporins are larger, more complicated molecules. 04: Ceftaroline, has excellent MRSA coverage, and we will often use it in patients who are sick with MRSA. 04: This is another agent. 04: You can see it's a slightly simpler structure. 04: It has powerful antipseudomonas activity, and it also can work against VRE, which stands for Vancomycin-resistant Enterococcus. 04: Ceftolozane is another fifth generation cephalosporin. 04: We will often use this in intraabdominal infections that are complicated. 04: So intra abdominal infections tend to have a lot of gram-negative organisms. 04: They sometimes have gram-positive organisms. 04: And more importantly, they have anaerobic organisms. 04: And treating anaerobic organisms is notoriously difficult. 05: We have to resort to very complicated drugs.
We've talked about the cephalosporins let's move on to the penems. 00: When you talk to your professors sometimes, they'll refer to penems as carbapenems but that's not quite technically correct. 00: Penems include both of the sulfapenems and the carbapenems. 00: The first of the sulfapenems is faropenem, which is not available in the USA. 00: Faropenem is an orally active unsaturated beta-lactam antibiotic. 00: It's resistant to many different forms of extended spectrum beta-lactamases, so when we have agents that are failing because the bacteria is producing beta-lactamase, we can use this agent and it tends to work quite nicely. It has better chemical stability than most agents and the nice thing about this particular agent is we now have trials that show that in tuberculosis it was effective. 00: We start treating patients in our community acquired pneumonia clinics with this agent and we're starting to see some people who have pulmonary TB being treated with faropenem. 01: The carbapenems are probably quite familiar to you already. 01: The most popular and most well-known of the carbapenems is imipenem. 01: You've probably seen it used on your clinical rotations. 01: When I was a resident this drug was just coming in and we used to nickname it guerillacilin because it was so powerful. 01: It's chemically unique but it still has a beta-lactam ring so we sometimes worry about beta- lactamases.
However, it does have a low susceptibility to those penicillinases so we can take some comfort in that. 01: Unfortunately, it is susceptible to a different kind of enzyme produced by the kidney called dehydropeptidase. 01: It's administered with cilastatin which is an inhibitor of that enzyme so we will see it administered as imipenem cilastatin. 01: It's a wide ranging agent. We tend to use it against all kinds of organism that includes the gram positive cocci, the gram-negative rods, the anaerobic confections are often treated including intra-abdominal infections, and then of course it's active against pseudomonas and the Acinetobacter species as well, so you can see where in patients who are in the intensive care unit, let's say they're brought in with pneumo sepsis and they have a bleeding gut, imipenem is often used in this kind of a patient because we're really not sure what is going on in the patient so we wanna broad-spectrum powerful agent that has pseudomonas activity. Monobactams, Cyclic Lipopeptide and Polypeptide – Cell Wall Synthesis Inhibitors (Antibiotics) 00: Cell wall synthesis inhibitors also include a broad spectrum of other agents, one of them are the monobactams. 00: Now monobactams include drugs like aztreonam. 00: Aztreonam has some adverse effect associated with it including GI upset and vertigo and headache, but the reason why we really like this particular agent is that it doesn't have any cross allergy with penicillins so when you have a patient come in who would really benefit from a penicillin but is allergic to penicillins we can use aztreonam. 00: The next category are cyclic lipopeptides.
Again, the nice things about these miscellaneous agents is that there isn't a cross reactivity in terms of patients who are penicillin allergic. 02: Daptomycin is kind of a fun agent to see how it works. 02: Daptomycin is this complex molecule with the stringy end that inserts into the cell wall. 02: Now it's complicated and it's huge as that molecule is it's not done because now it'll bind to a whole bunch of other daptomycin molecules and it will form something called oligomers or oligomerization. 02: Oligomers are when you have one drug binding to itself multiple times to form a complex. 02: This complex becomes a channel in the wall of the bacteria. 02: What happens with this channel is it get ion efflux. 02: That ion efflux causes a depolarization of the membrane. 02: Why do you care if the membrane is depolarized? Because if a bacterial membrane is depolarized, DNA and RNA synthesis cannot start or cannot proceed and that means that protein synthesis also can't proceed which means that the cell stops producing those proteins that are necessary for life the cell stops, the bacteria stops. 03: Let's move on to a different class called the cyclic polypeptides. 03: Cyclic polypeptides are also very complicated. 03: They are locally effective and they are often are limited to topical use. 03:
Topical doesn't just mean the skin because in this particular case we'll use this agent in sore throats. 03: We'll often will spray at the back of the throat if a person has an infection in the back of the throat only and it'll act locally to affect exchange. 03: Now, people like me love these kinds of drug not because they are particularly useful in the clinic but because they are so complicated and they are fun to look at. 03: Now this drug will inhibit protein biosynthesis of gram-positive organisms. 03: If you think about that, that's mostly the upper respiratory track, isn't it? They are also and this is important, completely ineffective against gram negative organisms so if you suspect a patient having a gram negative organism as a cause of the infection, don't use this particular agent.
Glycopeptide and Intracellular Agents – Cell Wall Synthesis Inhibitors
(Antibiotics)
We also have some glycopeptide antibiotics, the most commonly known of the glycopeptide type antibiotics is vancomycin and I've mentioned it in some of my other lectures. 00: Vancomycin is a bactericidal glycopeptide antibiotic. It binds to the peptidoglycan in the cell wall itself. 00: It binds to the alanine terminal and it acts as a stop function in cell wall synthesis. 00: One of the downsides of this particular agent is that if the organism has an altered alanine terminal on its NAM, it will now allow vancomycin to bind therefore, in these particular bacteria
Vancomycin infusion reaction is essentially a severe cutaneous reaction where you have tremendous flushing people turn a bright red and it's often because of histamine release. 02: You will also get other side effects in this medication including phlebitis, ototoxicity, and some nephrotoxicity as well. 02: Teicoplanin is another drug in this drug class. 02: Teicoplanin is even more complicated than vancomycin in structure and in fact, when you take a look at the structure here on the slide, you will see that there's a red R way up in the corner, that R can be many different groups, it could be a whole chain of structures so it's not just what you are seeing on the screen here today, it's actually a much more complicated molecule than what I'm showing you. 02: Now teicoplanin is used in prophylaxis, it's not really used in a lot of clinical practice. 03: It's used for treatment of methicillin resistant staph aureus and methicillin resistant enterococcus faecalis. 03: It's also used for the treatment of pseudomembranous colitis and in clostridioides difficile diarrhea. 03: Alright, we're almost done. I have one more to show you. 03: Let's take a look at this drug. This is called bacitracin. 03: Bacitracin is very commonly used in the prevention of certain types of infections and we often will use it as a prophylactic measure on the wards. 03: It's a bactoprenol inhibitor.
It's used in the topical treatment of certain types of infections and it's used in decontamination syndromes. 03: It's used in staph colonization of the skin, so sometimes you'll see dermatologist using it for particularly bad superficial infections. 03: One of the problems with bacitracin taken intravenously or parenterally is that it causes nephrotoxicity and because of that and because we have other agents that can do the job just as well, we tend not to use it intravenously or what we call parenterally. 04: We prefer instead just to use it on the surface of the skin and you'll see it often used on the wards when you have an MRSA outbreak. 04: Okay, that's it, well done good luck on your exams, you're gonna do well.
Linezolid, Streptogramins and Chloramphenicol – Bacterial Protein
Synthesis Inhibitors (Antibiotics)
So, let's talk about that last one linezolid.
They're used in drug-resistant gram-positive cocci infections like,
Methicillin-Resistant Staph Aureus, Penicillin Resistant Strep-Pneumo
and Vancomycin-Resistant Enterococcus.
They bind to the 50 S ribosomal unit as I had mentioned before, there
is no cross resistance with other protein synthesis inhibitors and
they're reserved for multi-drug resistant agents.
