Macrolide Flashcards
Be able to explain the polyketide biosynthesis pathway.
a) Macrolide antibiotics are polyketides because they are produced by sequential addition of propionate groups to a growing chain. This results in methyl groups on alternate carbon atoms in the macrolide ring.
b) Polyketides are biosynthesized through the condensation of simple building blocks, primarily acetyl-CoA and malonyl-CoA.
Be able to explain why macrolide antibiotics have methyl groups on alternating carbon atoms.
a) Because they are produced by sequential addition of propionate groups to a growing chain, resulting in methyl groups on alternate carbon atoms in the macrolide ring.
b) Alternating condensation steps incorporate methylmalonyl-CoA and malonyl-CoA resulting in methyl groups being added to alternating carbon atoms.
Be able to describe how the solubility of erythromycin is increased.
a) The amine in erythromycin can form salts that are more soluble. Erythromycin is converted into salts by reacting it with acids: glucoheptonic acid or lactobiononic acid.
Be able to describe how macrolide antibiotics work (mechanism of action).
a) Macrolides inhibit bacterial protein synthesis by binding reversibly to the P side of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA from the A site to the P site.
c) Macrolide binding mainly involves the bacterial 23S RNA and not the protein.
Be able to enumerate the mechanisms by which bacteria can become resistant to macrolide antibiotics.
a) 4 mechanisms of resistance:
i) Lactone ester hydrolase induced to degrade the macrolides by hydrolysis of the macrocycle.
ii) Drug-induced production of an RNA methylase. A specific adenine base (A2058) on the 23S RNA molecule of the 50S ribosomal subunit is methylated. This inhibits the binding of macrolides to the 50S subunit (methylation of A2058 on RNA prevents binding of erythromycin to 50S subunit).
iii) Mutation of adenine to guanine at the specific site A2058. Resulting in a reduction in binding of erythromycin and clarithromycin to the 23S rRNA.
iv) An efflux pump ejects the drugs from the cell by an active transport process.
Be able to recommend ways in which the incidence of macrolide resistance can be minimized.
a) Reduce the frequency of macrolide use.
Be able to explain why resistance to macrolide antibiotics by Pseudomonas spp. And Enterobacter spp. cannot be avoided.
a) Because they exhibit intrinsic resistance by not allowing entry of these drugs. There are specific genes associated with these organisms that confer this intrinsic resistance.
Be able to explain how acidic conditions can inactivate erythromycin, and how this has been overcome with some of the newer macrolide antibiotics.
a) It can be inactivated under acidic conditions by a process involving the 6-OH and 12-OH groups. The reaction is an intramolecular acid-catalyzed ketal formation. The ketal reaction product is inactive.
b) Acid stability can be achieved with the 6-OCH derivative, which enhances oral absorption (replace 6-OH with OCH3). This ether derivative blocks ketal formation at low pH. This antibiotic is clarithromycin.
c) Azithromycin, an amine analog, is acid stable and has reliable absorption. In this analog an N-methylated methyleneamino moiety replaces the C-9 ketone, so ketal formation is no longer possible (N-CH3 replaces the carbonyl carbon).
Be able to describe the metabolism of erythromycin and the effect that it has on biological activity.
a) Main route of erythromycin metabolism is demethylation in the liver.
The N-demethylated metabolite is narrower spectrum and less active
12) Be able to describe the basis for drug interactions with the macrolide antibiotics, and which macrolides are more likely to be involved in drug interactions.
a) Erythromycin and clarithromycin bind and inhibit CYP3A and related P450 isozymes.
b) In the case of rifampicin and rifabutin, these decrease the activity of erythromycin. All other interactions increase the drugs’ activities.
azithromycin not affected
Be able to describe the antibiotic spectrum of the macrolides, and their main clinical uses.
a) Erythromycins are primarily used for infections of skin and soft tissues primarily cause by gram-(+) bacteria.
Be able to list the main side effects of the macrolide antibiotics.
a) Relatively safe. Vomiting, gastric cramps, abdominal pain, allergic skin reactions can range from urticaria (hives) to anaphylaxis.
b) Stevens-Johnson syndrome and toxic epidermal necrolysis are serious SEs.
c) Long-term use can induce a reversible cholestatic hepatitis.
d) Erythromycin increases the probability of pyloric stenosis in kids whose mothers took the drug during late stages of pregnancy/while nursing.
Be able to explain why erythromycin dosage forms for oral administration are given as either enteric coated or as more stable salts or esters.
a) Because it is inactivated under acidic conditions by a process involving the 6-OH and 12-OH groups. The reaction is an intramolecular acid-catalyzed ketal formation. The ketal reaction product is inactive. So, it must be given as enteric coated tablets or as more stable salts/ethers to enhance its acid stability and protect it from acid-mediated degradation.
b) To prevent inactivation by gastric acids.
Be able to describe the role that phagocytes have in the delivery of erythromycin to the site of action.
a) Erythromycin is very rapidly absorbed and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, it is actively transported to the site of infection, where during active phagocytosis, large concentrations of erythromycin are released. Therefore, the phagocytes provide a very efficient drug delivery mechanism.
Be able to describe why clarithromycin is stable under acidic conditions, and what effects this has on oral absorption.
a) It has enhanced oral absorption due to replacing 6-OH with OCH3, stabilizing it in acid by preventing the formation of a ketal.
Be able to explain why clarithromycin produces less gastrointestinal cramping than erythromycin.
a) Because it has enhanced oral absorption due to replacing 6-OH with OCH3, stabilizing it in acid by preventing the formation of a ketal. This ketal reaction product is inactive and is what produces the GI cramping.
Be able to describe why azithromycin is stable in acid and erythromycin is not.
a) Because it has an N-methylated methyleneamino moiety that replaces the C-9 ketone, so ketal formation isn’t possible.
