Lecture 24 Flashcards
What is the function of tetracyclines?
Block binding of AA-tRNA to A site
What is the function of macrolides?
Block translocation
What is the function of linezolid?
Prevents binding of fMet-tRNA
What is the function of fusidic acid?
Inhibits elongation factor G
What is the function of chloramphenicol?
Blocks peptide bond formation
What is important about the macrolide structure?
Have large macro-cyclic ring structure w/ a lactone and often w/ methyl/ethyl groups on alternating carbons in the ring
Macrolide rings come in ____ member varieties
14, 15, and 16
What is normally attached to the ring structure of macrolides and through which bonds?
- At least one 6-membered amino-sugar and one 6 membered sugar
- Glycosidic bonds
What do macrolides bind to?
50S subunit of bacterial ribosome, making interactions btwn proteins and 23S rRNA
Where are the most significant interactions btwn macrolides and 50S subunit of ribosome?
In the peptidyl transferase ring region of the 23S rRNA
Do macrolides block peptidyl transfer?
No
What effect do macrolides have on peptidyl transfer?
Binding in the peptidyl transferase region results in inhibition of translocation of aminoacyl-tRNA => preventing protein synthesis
Macrolides are substrates for _____
CYP 3A4 N-dealkylation
What is important about the spiroketal form of macrolides?
- No antibiotic activity
- Binds w/ high affinity to motilin receptors in the gut, stimulating smooth muscle contraction and increasing gut motility => diarrhea
What is erythromycin often used for w/ respect to the gut?
To increase gastric motility
What is significant about erythromycin base?
Poor water solubility and is acid labile
What is significant about erythromycin HCl?
Improved water solubility and is acid labile
What is significant about erythromycin ethylsuccinate?
- Ester increases absorption of erythromycin compared to free base
- Better tolerated
- More acid stable than erythromycin
- Absorbed as ethylsuccinate ester, so must be hydrolyzed for activity
What is significant about erythromycin estolate?
- Propionic acid ester w/ lauryl sulfate counter ion
- Improves absorption in gut
- Better tolerated
- Propionic acid ester must be hydrolyzed for activity
- More acid stable than erythromycin
Do esters of erythromycin cause less diarrhea?
No, as erythromycin is excreted in the bile back into the gut, the esters still cause diarrhea
Which organisms is erythromycin effective against?
- Some gram pos (strep. pyogenes and pneumoniae)
- Variable activity against MSSA
- Limited gram neg activity and some anaerobes
When is erythromycin a good choice?
As an alternative where amoxicillin can’t be used due to an allergy
Is erythromycin commonly used? Why or why not?
No, clarithromycin is used more often b/c has longer half life, and doens’t form spiroketal so doesn’t cause diarrhea
What is clarithromycin used to treat and why?
- Mycoplasma pneumoniae
- Legionella pneumophila
- Both bacteria lack a cell wall so beta-lactams are ineffective
When is azithromycin used?
- Same indications as clarithromycin
- As an alternative to penicillin’s like amoxicillin in the case of an allergy
What is significant about azithromycin?
Extremely long half life, so need to give a loading dose
What can macrolides cause inhibition of?
CYP 3A4 by competition for the enzyme
What is the most important drug interaction w/ macrolides?
Warfarin
What are some drug interactions w/ macrolides?
- Carbamazepine
- Cyclosporine
- Theophylline
- Warfarin
- HMG-CoA reductase inhibitors
What do tetracyclines bind to and what does this cause?
- 16S rRNA of the 30S subunit of the bacterial ribosome
- Results in blocking the aminoacyl-tRNA from the A-site of the ribosome
What bacteria are tetracyclines effective against?
Very broad spectrum (many gram pos and gram neg and anaerobes)
___ properties of tetracyclines are essential for activity
Mg chelation
Are chelates of tetracyclines well absorbed?
No
What should be avoided and how long before and after taking tetracycline chelates?
- Dairy products, antacids, and supplements w/ calcium, magnesium, iron, and aluminum
- 1h before and 2h after dose
What does calcium chelation of tetracyclines cause?
Causes tetracyclines to be incorporated into newly forming bones and teeth as tetracycline-calcium orthophosphated complexes => brown discolouration or streaks on teeth
Are tetracyclines safe in pregnancy and lactation?
No, cross placenta and get into breast milk
In which px should tetracyclines not be used?
- Pregnant women
- Children 12 and under
What are the 2 commonly used tetracyclines?
Doxycycline and minocycline
What is the spectrum of doxycycline?
- Activity against many gram pos, MRSA, and MSSA; many gram neg and anaerobes
- Not against VRE or VRSA
- Used as an alternative to amoxicillin when allergy is present and against mycoplasma pneumoniae and legionella pneumophila
What is the spectrum of minocycline?
- More broad than minocycline
- Gram pos including MSSA and MRSA
- More gram neg and anaerobes
- Good alternative to amoxicillin when allergy is present and against mycoplasma pneumoniae and legionella pneumophila
What is the spectrum of tigecycline?
- All gram pos including MSSA, MRSA, and VRSA (not VRE)
- Most gram neg and anaerobes
When is tigecycline used?
As a very last resort b/c of side effects
What are some side effects of tetracyclines?
Erosions of epithelium => irritation to tissues and photosensitivity
Which location is most susceptible to tetracycline side effects and how can this be prevented?
- Esophagus
- Take dose w/ full glass of water and do not lie down for at least 1/2 hour after a dose
How can a bacteria produce macrolide resistance?
- Produce a gene that methylates the A2058 (causes steric hindrance for macrolide binding)
- Mutation of A2058 to G (reduces # of potential H-bond interactions)
What makes macrolides lethal for bacteria but harmless for humans?
Bacterial ribosomes have A2058 while human ribosomes don’t
