Protein Synthesis Inhibitors Flashcards
Bacterial ribosomes
70s
30s and 50s subunits
50s subunits have 23s rRNA
30s subunits have 16s rRNA
Human ribosomes
80s
40s and 60s subunits
Protein synthesis inhibitors selective toxicity
Human ribosomes are different from bacterial ribosomes. Drugs selectively target bacterial ribosomes. However, at higher drug concentrations, drugs can bind to human ribosomes.
TCN and aminoglycosides: taken up by active uptake=> contributes to selective toxicity b/c it does not occur in human cells
50s protein synthesis inhibitors
“Buy AT 30, SELL at 50”
MaCROlides and Ketolides (ErythROMYCIN, ClarithROMYCIN, AzithROMYCIN, TelithROMYCIN)
LINcosamide (cLINdamycin)
Streptogramin (Quinupristin/Dalfopristin)
OxaZOLIDone (LineZOLID)
Chloramphenicol
30s protein synthesis inhibitors
“Buy AT 30, SELL at 50”
Tetracyclines (Tetracycline, Doxycycline, Minocycline)
Glycyclines (Tigecyclin)
Aminoglycosides (Streptomycin, Tobramycin, Gentamicin, Amikacin, Neomycin)
Tetracyclines
Inhibit bacterial protein synthesis by binding to 30s subunit and preventing binding of aminoacyl tRNA to mRNA complex. TCN interacts with 16s rRNA
Bacteriostatic
Broad spectrum: gram (+/-), spirochete a, mycoplasms, rickettsiae, and chlamydiea
Therapeutic uses: cholera, *Lyme disease, Rocky Mountain spotted fever, mycoplasma pneumonia (atypical: no cell wall so PCN won’t work), *management of acne
Tetracycline bacterial resistance
Common. Plasma mediated. Cross resistance w/in drug class (if resistant to Doxycycline, will also be resistant to Minocycline)
Decreased TCN accumulation:
-Reduced permeability
-Increased efflux: tetK gene (E. Coli and S. Pneumoniae have gene)
Altered target (tetM)
-Production of ribosomal protection protein–>displaces TCN from target. Cross resistance occurs
Enzyme inactivation (tetX): not common
-Inactivate TCN in presence of NADPH and O2
6-deoxy TCN drugs
Doxycycline and Minocycline
6-deoxy: more lipophilic, increases oral absorption, increases acid stability
TCN physio-chemical properties
Conjugated double bonds give yellow color=> accumulates in teeth and bones. Avoid in kids developing permanent teeth
Amphoteric: exists as acid or base
Chelation with polyvalent metal ions: form insoluble complexes
Phototoxicity from C7-chloro group
Do not administer TCN with…
Milk Iron Vitamins Bismuth salts Antacids Vitamins Metal ions Hemetics Cholestyrmine or cholestipol Take TCN one hour before or two hours after taking any of the above Oral absorption is impaired by food or meds containing di or trivalent metal ions (except doxycycline and Minocycline-->can still chelate but absorption not affected)
Chemical stability of TCN
Dimethylamino group must be in alpha orientation ( essential for activity)
TCN undergoes epimerization between pH 2-6. Can change orientation and make inactive
Or it can undergo dehydration at C6, than epimerization. The 4-epianhydroTCN is inactive but toxic to kidneys leading to Fanconi syndrome. Doxycycline and Minocycline are free of this toxicity b/c of 6-deoxy structures.
Distribution of TCN
Minocycline is only one that can penetrate CSF
All cross placenta and breast milk
All penetrate the enamel of unerupted teeth
TCN DDIs
Cyp inducers increase metabolism of doxycycline
PCN: decrease PCN bactericidal effect. TCNs are bacteriostatic. PCN works on cell walls and needs rapidly growing bacteria in order to work, TCN stops reproduction and growth
Retinoic acids: cerebral hypertension
Adverse effects of TCN
GI upset Photosensitivity Chelation with metal ions Depressed bone growth in neonates Teeth discoloration in children Hypersensitivity rxn: rash (Steven Johnson's syndrome) Superinfection: from C. diff overgrowth
Glycycline (Tigecycline or Tygacil)
T-butylglycylamido group at C9 enhances bindings to 30s subunit (increase antibacterial activity)
Broad spectrum: gram (+/-) also MDR bacteria such as pseudomonas
Bacterial resistance: rare–>*avoids TCN resistance from enhanced affinity to binding site and t-butylglycylamido group provides steric hindrance to avoid efflux protein
Streptomyces suffix
Aminoglycosides
Mycin
I.e: neomycin, streptomycin
Micromonospora suffix
Aminoglycosides
Micin
I.e. Gentamicin
Structure of aminoglycosides
Amino sugars linked glycosidically
At least one aminohexose sugar: N-Methyl-L-glucosamine
Highly substituted 1,3-diaminocyclohexane ring (aminocyclitol): streptidine
Aminoglycoside MOA
Inhibition of bacterial protein synthesis by binding to 30s ribosome subunit-> form a complex that is unable to initiate proper amino acid polymerization
Bactericidal
-blocks initiation of protein synthesis
-blocks further translation and elicits premature termination
-incorporation of incorrect Amino acid
Aminoglycoside antibacterial activity
Only against aerobic bacteria (taken up by active uptake)
Broad spectrum: gram(+/-) bacteria but reserved for more serious gram (-)
Aminoglycosides and beta lactam Abx are synergistic (both bactericidal) but incompatible (Aminoglycoside Inactivates beta Lactam by opening up beta Lactam ring)
Aminoglycoside bacterial resistance
Through horizontal gene transfer from resistant plasmids
N-acetylation
O-phosphorylation
O-adenylation
Bacteria resistant to Aminoglycosides may be susceptible to Amikacin b/c of 2-hydroxyaminobutyric acid tail Inactivates all modifying enzymes
Insufficient accumulation of drug: reduced permeability or enhanced efflux
Mutation of drug target: 30s ribosome
PK of aminoglycosides
Poor oral absorption. Used Parenteral or topical
Neomycin black box warning: if applied on denuded skin in sufficient quantities it can lead to systemic toxicity
Short half life but post antibiotic effect
Ototoxicity and nephrotoxicity (similar to vancomycin, do not administer together)
Neuromuscular blockade
Post antibiotic effect
See antibacterial effect even after [serum drug] concentration falls below MIC
Macrolide and Ketolide structure
Large lactone ring
Ketone group
Glycosidically linked amino sugar (desosamine)
Neutral sugar linked either to amino sugar or to lactone ring (cladinose)
