Peptidoglycan – Beta Lactam Antibiotics

by Adam Le Gresley, PhD

My Notes
  • Required.
Save Cancel
    Learning Material 2
    • PDF
      Slides 14 Chemistry Advanced Le Gresley.pdf
    • PDF
      Download Lecture Overview
    Report mistake

    00:01 So, let’s talk about how it actually works. It works by targeting peptidoglycan. Peptidoglycan is a mixed heteropolymer of hexose sugars and amino acids which effectively surrounds a bacterium like a net. The sugars are made up of N-acetylglucosamine, which is abbreviated NAG, and N-acetylmuramic acid, abbreviated NAM. And they’re linked alternately in a chain or polysaccharide. Attached to the NAM or N-acetylmuramic acid are short peptides.

    00:40 So, let’s have a quick look of what this means from a physiological perspective to some extent.

    00:47 Here we’ve got an example of two types of bacteria. On the left hand side, we have the Gram-positive and on the right hand side, we have the Gram-negative. And these are broad classifications of bacteria that are encountered.

    01:01 Gram-positive bacteria, for example, such as Staphylococcus Aureus, and Gram-negative bacteria, for example, Pseudomonas Aeruginosa. So, let’s have a look at the differences between the two.

    01:15 If we zoom into the cell wall in both types of bacteria, we see that the cell wall in Gram-positive bacteria has a very thick layer of peptidoglycan (shown in purple) that protects the cell membrane.

    01:28 If we look on the right-hand side, we see that the cell wall in Gram-negative bacteria has a lipopolysaccharide, which is over the top of the outer membrane and thin peptidoglycan layer.

    01:40 This does or has presented a problem with the use of penicillins in the treatment of Gram-negative bacterial infections. But, we’ll come onto that a little later on.

    01:48 So, being aware of this and being shown this in cartoon form, what I’d like to now do is drill down into the details of the structure of the peptidoglycan. And this brings me to the next slide.

    02:00 Here we have balls representing the N-acetylmuramic and the N-acetylglucosamine shown as NAM and NAG respectively. Here we show that the NAM units are linked together with NAM units on adjacent chains by the short peptide bridges. Now, this is a good cartoon structure which makes you understand how the layers of peptidoglycan are built up around bacteria. But, it does nothing in terms of explaining what’s happening on a molecular level. So, let’s zoom in a little more.

    02:35 If we zoom in a little more and we look at our NAG-NAM backbone, which we showed as the alternating balls of our sugar backbone, we can see that the linkers are constituted of a variety of different amino acids shown here: L-Alanine, D-Glutamate, L-Lysine, followed by this pentaglycyl polypeptide which links to, again, D-Alanine, L-Lysine, D-Glutamate and L-Alanine. And it’s this chain here which is the important point of action for our target enzyme.

    03:12 What do I mean by that? Irreversible inhibition of the enzymes involved in cross-linking peptidoglycan is the main mode of action for penicillins. Transamidase, which is a penicillin-binding protein cleaves between two D-Alanine-D-Alanine amino acids at the end of the peptide from the N-acetylmuramic acid (NAM). Attack by the free amino end of a pentaglycyl unit of an adjacent peptide thus forms a crosslink between the two linking the chains together.

    03:50 So, let’s have a look at a diagram since, sometimes, a mechanism speaks a thousand words.

    03:55 What’s happening in this particular case is that the enzyme or penicillin-binding protein activity is cleaving off that terminal D-Alanine and activating the one next to it. What then happens is the pentaglycyl unit from a neighbouring chain creates an amide bond or peptide bond between itself and that penultimate D-Alanine. This results in the cross-linking of the two chains. Now, we have two sugar backbones held together by a polypeptide bridge and it’s this structural integrity that the penicillin-binding protein is responsible for. And it is this part that is responsible... that penicillins are shown to inhibit.

    04:45 Okay. So, we’ve actually looked at it from an amino acid perspective and that’s fine.

    04:48 But, let’s drill down even further and start looking at it from a proper molecular perspective.

    About the Lecture

    The lecture Peptidoglycan – Beta Lactam Antibiotics by Adam Le Gresley, PhD is from the course Medical Chemistry.

    Included Quiz Questions

    1. Penicillin antibiotics help bacteria to synthesize a layer of peptidoglycan around their cell membranes.
    2. The sugar molecules and amino acids polymerize to form a polymer of peptidoglycan, a component of bacterial cell wall.
    3. Peptidoglycan consists of alternative residues of β-(1,4) linked N-acetylglucosamine and N-acetylmuramic acid.
    4. The lipopolysaccharide layer associated with a thin layer of peptidoglycan in gram-negative bacteria creates a problem in the treatment of infected patients with penicillin antibiotics.
    5. Gram-positive bacteria have thicker layers of peptidoglycan than Gram-negative bacteria.
    1. Peptide bridges
    2. Hydrogen bonds
    3. Hydrophilic forces
    4. Nuclear forces
    5. Electrostatic forces
    1. Irreversible inhibition of enzymes involved in cross-linking of peptidoglycan.
    2. Reversible inhibition of enzymes involved in cross-linking of peptidoglycan.
    3. Reversible inhibition of enzymes involved in synthesis of N-acetylmuramic acid.
    4. Irreversible inhibition of enzymes involved in synthesis of N-acetylglucosamine.
    5. Irreversible inhibition of enzymes involved in bacterial division.
    1. The cleavage between two D-ala-D-ala residues at the end of the peptide chain.
    2. The cleavage between NAG and NAM units.
    3. The depolymerization of amino sugar chains.
    4. The cleavage between terminal Gly-Gly units.
    5. The cleavage between D-glu-L-lys residues.

    Author of lecture Peptidoglycan – Beta Lactam Antibiotics

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD

    Customer reviews

    5,0 of 5 stars
    5 Stars
    4 Stars
    3 Stars
    2 Stars
    1  Star
    Well explained details on mechanism of action --> also relates to vancomycin mechanism of action
    By Nicholas C. on 27. October 2019 for Peptidoglycan – Beta Lactam Antibiotics

    I watched the glycopeptide pharmacology lecture, wanted more details on the mechanism of action, segwayed to antimicrobial resistance, then segwayed to "Peptidoglycans - Beta Lactam Antibiotics" video lecture. The D-Alanine-D-Alanine concept also relates to the mechanism of action of vancomycin.