Protein Synthesis Inhibitors Flashcards
MOA of Protein Synthesis Inhibitors
Target bacterial protein synthesis
Directly interfere with: Initiation phase of protein synthesis Binding of tRNA Activities of peptidyl transferase AA insertions--> misreading error
Macrolids, aminoglycosides, tetracyclines
Aminoglycosides MOA
Bind to 30S subunit
Interfere with formation of initiation complex
Misread mRNA and miscode AA’s in growing peptide chain
Cause ribosomes to separate from mRNA
Blockade of movement of ribosome
Amikacin
Aminoglycoside
Binds to 30S subunit
Gentamicin
Aminoglycoside
Binds to 30S subunit
Kanamycin
Aminoglycoside
Binds to 30S subunit
Streptomycin
Aminoglycoside
Binds to 30S subunit
Neomycin
Aminoglycoside
Binds to 30S subunit
Netilmicin
Aminoglycoside
Binds to 30S subunit
Tobramycin
Aminoglycoside
Binds to 30S subunit
Pharmacokinetics of Aminoglycosides
Parenteral administration–too water soluble for oral
Hydrophilic–marginal penetration of CNS
Toxicities of Aminoglycosides
Ototoxic
Nephrotoxic
(due to accumulation in inner ear or renal cortex)
Post-Antibiotic Effect
Aminoglycosides
Microorganisms continue to die despite declining plasma drug levels
Due to translational mechanism of action
Resistance of Aminoglycosides
ONLY used reliably in Gram -
Alter receptor on ribosome
Alter drug itself
Tetracyclines: drugs + MOA
Drugs– all end in “cycline”:
- Tetracycline, minocycline, doxycycline, demeclocycline, oxytetracycline, and tigecycline
Binding to 30 S ribosomal subunit
Prevents binding of incoming AA’s
Tetracycline: target organisms and resistance
Bacteriostatic against gram +/-
Differing modes of penetration:
Gram + = active transport; resistance: active pump out drug via efflux pump
Gram - = passive diffusion; resistance: alter outer membrane to prevent permeability
Tetracycline Pharmacokinetics
Take on empty stomach–gastric absorption inhibited by chelation
Renal dysfunction–use doxycycline–safest!
hepatic metabolism and fecal excretion
Tigecycline
Tetracycline–overcomes both methods of resistance in gram + and gram - bacteria
Doxycycline
Tetracyline
Safest to use if renal dysfunction
-Hepatic metabolism and fecal excretion
Chloramphenical
Binds 50S ribosomal subunit
Blocks linkage of AA’s in growing chain by interfering with peptidyl transferase
Metabolized via glucuronidation
Gray baby
“Gray baby”
Chloramphenical
Metabolized via glucuronidation–if this is inefficient, drug accumulates
Infants with failure to thrive, failure to eat
Pale and cyanotic
Lincosamides
Clindamycin
Binds 50S ribosomal subunit
Prevent’s AA translocation from A –> P site
Macrolides MOA
Binds 50S ribosomal subunit
Prevents translocation from A –> P site
Bacteriostatic/Bacteriocidal depending on concentration
Macrolides: Drugs
Erythromycin
Clarithromycin
Azithromycin
What 3 drugs share a binding site, and thus risk the development of cross resistance?
Clindamycin
Chloramphenicol
Macrolides
Adverse Effects of Macrolides
GI distress
Alter activity of other drugs (inhibits microsomal p450 3A4 metabolism)–> toxicity to other meds!
Prolongs QT interval
Clarithromycin
Macrolide
No GI distress
Still inhibits CYP 3A4
Prolongs QT interval
Azithromycin
Macrolide
NO GI distress
NO CYP 3A4 interference
NO QT prolongation
BUT due to cross sensitivity, may cause allergic reaction if patient is allergic to erythromycin
Ketolides
Telithromycin
Inhibits the 50S ribosomal subunit
Binds 2 separate domains–thus difficult for bacteria to develop resistance
Retapamulin
Binds 50S ribosomal subunit
interferes with peptidyl transferase
Blocks P site
Topical ointment
Mupirocin
NO cross resistance with other antimicrobials
inhibits tRNA that transports isoleucine
Topical cream/ointment
Linezolid
Binds 50S unique site
Prevents 70S complex formation
Streptogramins
Quinupristin: blocks ribosomes, inhibits late phases of protein synthesis
Dalfopristin: inhibits early phases of protein synthesis
