Exam 1- Cushman Lec 3- Macrolide Antibiotics Flashcards
What are the main parts of the macrolide structure?
14-membered lactone ring
Desosamine sugar is important for activity
Polyketides
What occurs in the polyketide synthesis pathway used for macrolide antibiotics?
Sequential addition of propionate groups to a growing chain
-results in methyl groups on alternate carbon atoms in the macrolide ring
Why is the solubility of erythromycin increased?
The pKa of the amine in erythromycin is 8.8
The amine can form salts that are more soluble
What is the moa of macrolides?
Recall: during peptide bond formation, the polypeptide attached to the tRNA in the P site of the ribosome is transferred to the amino group of the aminoacyl-tRNA in the A site (transpeptidation)
-ribosome then moves to the next codon
-empty tRNA is ejected and the peptidyl-tRNA is shifted from the A site to the P site (translocation)
-new aminoacyl-tRNA binds to A site
-macrolides inhibit protein synthesis by binding to P site and inhibiting translocation of peptidyl-tRNA from the A to P site
-some macrolides bind between the A and P site and obstruct peptide bond formation
What is the antibiotic action of macrolides?
Bacteriostatic
-can be bactericidal in high concentrations
What are the mechanisms of resistance against macrolides?
1) Lactone ester hydrolase
–degrade macrolides through hydrolysis
2) Drug-induced production of RNA methylase
–inhibits binding of macrolides to 50S subunit
3) Mutation of adenine to guanine at A2058
–reduces binding to 23S ribosomal RNA
4) Efflux pump
Which organisms have intrinsic (unavoidable) resistance to macrolides?
Pseudomonas spp
Enterobacter spp
How can erythromycin be inactivated by acidic conditions?
Process involving 6-OH and 12-OH groups
-intramolecular acid-catalyzed ketal formation
-ketal reaction product is inactive
Acid stability of macrolides can be achieved with what derivative?
6-OCH derivative (replace with OCH3)
this is clarithromycin
Why is azithromycin acid stable?
N-methylated methyleneamino moiety replaces the C-9 ketone
*makes ketal formation no longer possible
What is the main route of erythromycin metabolism?
Demethylation in the liver
-main elimination route is in the bile, small portion in the urine
What is the clinical use of erythromycins?
Infections of skin and soft tissue
*Gram + bacteria
What are the side effects of macrolides?
Generally safe
*14-membered macrolides stimulate GI motor activity and can cause vomiting, gastric cramps, and abdominal pain
Skin reactions
Cholestatic hepatitis can occur with long term use
–jaundice + cramping/nausea/fever
–relieved upon drug termination
*Erythromycin increases risk of pylenoric stenosis in children whose mothers tool the drug in late pregnancy stages or while nursing
How is erythromycin administered?
-Inactivated by gastric acids so po forms must be enteric coated
—otherwise they must be in more stable salt or ester forms
How does erythromycin reach a site of infection?
Erythromycin is found in high concentrations in phagocytes
-these actively transport it to the site of infection
