Antimicrobial Resistance

by Vincent Racaniello, PhD

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    00:01 Unfortunately, as we develop new antimicrobial compounds, resistance to them rapidly emerges.

    00:11 And today we have resistance to almost every antimicrobial compound that we have developed, and the situation is becoming dire because we have fewer and fewer options with which to treat bacterial infections. Antimicrobial resistance occurs in nature and it’s ancient.

    00:32 Bacteria make antibiotics to compete with each other in nature and many of those we have harnessed to use as antimicrobial treatments of infections of people. We know that these genes that confer resistance have been around for thousands and thousands of years, we can find them in very old sites on earth, and there is plenty of evidence that they existed way before human developed any antimicrobial compound, so we are really taking advantage of something that exists in nature. There are a number of mechanisms by which these antimicrobial genes or I should say antimicrobial resistance genes work. For example, they may direct the synthesis of an enzyme that breaks down the drug, a simple way of doing resistance, they may chemically modify the drug, so it interferes with its function, they could inhibit the uptake of the drug into cells and tissues, so it can no longer access its target, or they could stimulate the export of a drug from the bacterial cell, so it's no longer bactericidal, or they may modify the target site of the drugs. So there are many different mechanisms of antimicrobial resistance, and again these are all encoded on genes that code for proteins that have these various activities.

    01:54 Let's take an example to illustrate that, and we will use an example, the antibiotic, vancomycin. Its target is cell wall modification. So vancomycin acts by blocking the assembly of the murein cell wall. Now at the top of this slide is the normal incorporation of the precursors of murein, so the blue and the green ovals, those are sugar molecules that are going to be part of the growing peptidoglycan chain and these smaller ovals below them.

    02:32 Those are amino acids that will eventually cross-link the murein to make it very strong.

    02:36 So the way this works is that subunits are added to the growing chain, in the second row of this diagram, you can see the growing polypeptide chain. Vancomycin binds to the precursors by binding to the amino acid. Vancomycin is shown here in purple with the V, or maybe that's brown, and it's binding the amino acids and blocking the incorporation into the new chain, therefore this inhibits murein synthesis and kills the bacteria.

    03:04 Resistance to vancomycin, one mechanism of resistance is simply that the bacterium changes the D-ala-D-ala to D-ala-D-lac, and lactose can be incorporated into this chain, it evades vancomycin resistance, and the antibiotic no longer works. That's one example of the way resistance works. Going back to our β-lactam antibiotics, which I mentioned before, and the arrow points to the β-lactam ring, that's common to all members of this class, that's why we call them β-lactams. We have so far identified over 300 β-lactamases. These are enzymes that cut that β-lactam ring, and these β-lactamases encode resistance to the β-lactam antibiotics. So you can see the extent of the problem, β-lactamases are everywhere.

    04:09 Further complicating antibiotic resistance, is that the genes encoding resistance factors, for example that encode β-lactamases, are often able to move from bacterium to bacterium.

    04:26 One way to do that is via plasmids and in fact many of these antibiotic resistance genes are encoded on plasmids. This diagram, which we saw previously in one of our other lectures, shows how plasmids can move from one bacterial cell to another. In the upper left is a bacterial cell with a chromosome in green and a smaller plasmid in red. Let's say this plasmid encodes a β-lactamase, which confers resistance to beta-lactams to that bacterium, well in the second set of bacteria, the two bacteria are now exchanging DNA through a pilus that's joining the two cells, and the plasmid is moving from one cell to another. The result is that that second cell now acquires antibiotic resistance. So you know a problem here is that we often feed our animals that we eat for food lots of antibiotics so they grow up quickly. The effect is that we select for antimicrobial resistance in the animals and then when we eat these foods, we acquire antibiotic resistance genes in us, which are of no consequence initially, but then when we go to have surgery and we need antibiotic therapy, it doesn't work, because we have the resistance already in us. So these antibiotic resistance genes can move around bacteria extensively, this is why they're a problem, not just by plasmid mobility, but by also movement by transduction, the exchange of pieces of DNA by viruses or simply by naked DNA. So gene transfer among bacteria, we call this horizontal gene transfer, is widespread and is a big problem for antimicrobial resistance.

    06:09 Let's end up with a chart showing you some common mechanisms of resistance to antimicrobial agents, for example the penicillins and the cephalosporins are hydrolyzed by β-lactamases which we mentioned, these resistance genes are in fact carried on plasmids. Methicillin resistance is a change in the penicillin binding protein, not in a β-lactamase, but in a separate protein, this happens not to be carried on a plasmid. Tetracycline resistance encodes a pump that pushes the drug out of the bacterial cell; this is a plasmid born resistance factor.

    06:46 So if you look at all these various mechanisms of resistance modification of the drug, synthesis of alternate substrates, and so forth, acetylation, change in binding sites, look how many are encoded on plasmids and that simply means that they are easy to go from bacterium to bacterium, and we have a hard time treating bacterial infections when these resistance genes are so mobile.

    About the Lecture

    The lecture Antimicrobial Resistance by Vincent Racaniello, PhD is from the course Bacteria.

    Included Quiz Questions

    1. Genetic mutation resulting in a lack of vancomycin binding site
    2. Increased D-ala-D-ala synthesis
    3. Decreased peptidoglycan wall synthesis
    4. Decreased bacterial utilization of lactose
    5. Increased synthesis of beta-lactam ring
    1. Cephalosporins
    2. Tetracyclins
    3. Vancomycin
    4. Flouroquinolones
    5. Linezolid
    1. Efflux pump
    2. Acetylation
    3. Enzymatic modification
    4. Change in peptidoglycan binding site
    5. Beta-lactamases

    Author of lecture Antimicrobial Resistance

     Vincent Racaniello, PhD

    Vincent Racaniello, PhD

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    Excellent doctor. Thank you.
    By Sanjib K. on 17. May 2018 for Antimicrobial Resistance

    short and sweet concepts. nice tables. easy to understand. thank you.