As promised in my last post, this post will discuss antibiotics in more detail!
Explain key concepts relevant to the action of antibacterial drugs, including spectrum of action, mechanism of action, individuation of dosing, drug resistance, etc.
Uhh, I'm fairly sure I've done this already...
Show awareness of major drugs such as the penicillins and related drug classes that interfere with the synthesis of the bacterial cell wall.
Firstly, a few points on what the bacterial cell wall looks like and how it is synthesised. Bacterial cell walls are made up of peptidoglycans, which are essentially lattices of glycan (sugar) chains. These chains are crosslinked by short peptide chains. The peptidoglycan layer varies in thickness depending on the type of bacteria- gram-positive bacteria have thicker peptidoglycans than gram-negative. (Gram-positive/negative simply refers to whether or not they are stained by Gram's stain.)
The actual cell wall production process is kinda complex, but the main gist of it is that the cross-linking peptide chains are synthesised on the inside of the cell and are dragged across the cell membrane by binding to a 55-carbon lipid. While it's being dragged across, some other stuff gets added, including the crosslinking peptide chains. After being towed across the membrane, the crosslinking chains can do their job and crosslink stuff, helped along by enzymes like transpeptidase.
The important part for you to know is that transpeptidase catalyses crosslinkages, and without crosslinkages a stable cell wall does not form. β-lactam drugs, so called because they have a 4-carbon β-lactam ring, form covalent bonds with transpeptidases, irreversibly stopping them from forming crosslinks. β-lactam drugs include the penicillins, the cephalosporins and the carbapenems.
There are several problems emerging with the use of penicillins. Firstly, people are developing allergies to penicillin. This is because the β-lactam ring of penicillin can open up to form penicilloic acid, which can then bind to other stuff, creating new and interesting antigens that some people's immune systems don't seem to like. Penicillin can result in some nasty allergic responses in these people.
Another problem with the use of penicillins (or with antibiotics in general) is the emergence of resistance. Bacteria can build up resistance to penicillin via the formation of β-lactamases (enzymes that break down the all-important β-lactam ring), stopping the drug from reaching the target area of the cell or by creating new proteins that penicillin can't bind to. The first mechanism of resistance that I mentioned, formation of β-lactamases, can be circumvented by the use of clavulanic acid. This is an irreversible inhibitor of β-lactamases. This is why amoxicillin (one of the penicillins) is often co-administered with clavulanic acid.
Show an understanding of the basic features of bacterial protein synthesis, including an appreciation for how specific antibacterial drugs block specific steps.
Protein synthesis inhibitors can inhibit pretty much every stage of the process of protein synthesis. (I have a post here specifically on prokaryotic protein synthesis, though it might be too much detail for the purposes of this post.) The four main types that I am going to talk about are the aminoglycasides, tetracyclines, amphenicols and macrolides.
Aminoglycosides are amino sugars (amino = amino, glyco = sugar). As both amino groups and sugars tend to be quite polar and hydrophilic, they don't cross cell membranes so well and thus they tend to have poor absorption. Their mechanism of action is by binding to the decoding site on the 30S ribosome, leading to misreading of the mRNA template and the insertion of the wrong amino acid. This, in turn, leads to non-functional proteins, making things quite difficult for the bacteria. Aminoglycosides also happen to be bactericidal- they are the only bactericidal protein synthesis inhibitors (other protein synthesis inhibitors are bacteriostatic).
Tetracyclines have four rings (tetra = four, cycl = ring). They prevent tRNAs from binding to the mRNA-ribosome complex, halting protein synthesis.
Chloramphenicol (a major player in the amphenicols) binds to the 50S ribosomal subunit, preventing the formation of peptide bonds between adjacent amino acids.
Macrolides are fairly large molecules that bind to the 50S subunit, preventing the tRNA from moving from the A site to the P site (these sites are mentioned in a previous post). They do this by plugging up the "tunnel" within the ribosome.
A quick note on polymixins
These didn't really fit into the lecture outcomes, but since they were mentioned during the lecture, I might as well mention them here. Polymixins are antibiotics used pretty much of last resort as they are quite toxic. They are plasma membrane permeabilising agents that work by acting as a "detergent," disrupting the cell membrane by interacting with membrane phospholipids. Despite their toxic profile, they are making a bit of a comeback due to the rise of antibiotic-resistant bacteria.
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