Protein Synthesis Inhibitors: Tetracyclines, Chloramphenicol, Aminoglycosides Flashcards
what is the shared mechanism for all protein synthesis inhibitors?
- bind to ribosomal subunits: usually 30s or 50s
- inhibit formation of polypeptide chains and block protein synthesis
discovery of tetracyclines
Compound isolated from an “ultra mold” that was dug from a dormant timothy hayfield on the University of Missouri campus in Columbia, MO by Dr. Benjamin Duggar who was mining actinomycetes soil bacteria as a consultant for American Cyanamid searching for new antibiotics.
what is great about tetracyclines?
first true “broad spectrum” antibiotics discovered as they act against:
- Gram + and Gram - bacteria
- Mycoplasma
- some mycobacteria
- most alpha-proteobacteria: anaplasma, rickettsia
- protozoan and filarial parasites
tetracyclines are active against
- Gram + and Gram - bacteria
- Mycoplasma
- some mycobacteria
- most alpha-proteobacteria: anaplasma, rickettsia
- protozoan and filarial parasites
tetracyclines are first-line drugs in what species?
food animals, aquaculture species, exotic animals, honeybees
less often utilized in small animals, horses, humans
tetracyclines
tetracycline, oxytetracycline, chlortetracycline, doxycycline and minocycline
MOA of tetracyclines
bind to the 16s rRNA and S7 protein of the 30s ribosomal subunit: inhibits tRNAs from binding to the docking site on the ribosome and mRNA codon to block peptide synthesis
what other unique effect do tetracyclines possess?
anti-inflammatory activity: can inhibit matrix metalloproteinase enzymes by binding to structural Zn2+ and Ca2+ ions, and can scavenge ROS
tetracycline chemistry
- complexes with Mg2+, Zn2+, Fe2+
- zwitterionic forms
- ROS
are tetracyclines bacteriostatic or bactericidal?
in general, they are bacteriostatic, but there is some evidence for time-dependent bactericidal activity for doxycycline
how are tetracyclines administered?
- not very soluble in water, thus formulated as salts that can be given orally or parenterally
- ionized at all pH values, however a null net charge of zwitterionic form favors passage across cell membranes
what is the representative drug for sensitivity testing?
tetracycline
why is tetracycline the representative drug for sensitivity testing?
media stability
potency of this group of drugs increases with increasing lipid solubility
resistance of tetracyclines
numerous mechanisms have been ID
- energy dependent efflux systems that exchange an extracellular H+ for a drug-Mg2+ complex
- ribosomal protection proteins that remove the tetracycline from the binding site near the tRNA docking site = protective proteins bind and yank it out
- 16s rRNA mutation
PK properties of tetracyclines
- oral bioavailabililty is poor and is worse in presence of cations: reduced when given with milk replacer or antacids
- wide tissue distribution and are one of only a few OSTEOTROPIC antimicrobial drugs!!!
what type of abx are osteotropic?
TETRACYCLINES
cation-chelating properties lead to deposition in teeth and sites of new bone formation
how are tetracyclines excreted
glomerular filtration, some biliary secretion depending on lipid solubility
enterohepatic circulation leads to longer half-lives than most drugs eliminated thru the kidneys
why do tetracyclines have a longer half life even thought they are excreted thru glomerular filtration?
enterohepatic circulation leads to longer half-lives than most drugs eliminated thru the kidneys
toxicities of tetracyclines
- generally safe, but are irritants and may cause vomiting after oral dosing and tissue damage at injection sites
- cause imbalance of intestinal flora = enterocolitis
what medication is associated with esophageal stricture in cats?
doxycycline
doxycycline is associated with what sequela in cats?
esophageal stricture
what are some toxicoses you might see with tetracycline administration?
- acute heart toxicity following high dose, rapid IV injection: associated w ability to bind calcium
- renal toxicosis is possible, high dose therapy in foals
- yellow discoloration of teeth in growing animals!
what is a side effect of giving tetracyclines to growing animals?
yellow discoloration of teeth
what drug might cause yellow discoloration of teeth in growing animals?
tetracyclines
what is the primary indication of tetracycline use?
treatment of bovine and porcine respiratory disease complexes: tetracycline and oxytetracycline and long-acting formulations
what is the drug of choice for treating plague, tularemia and listeriosis?
tetracyclines
what is the drug of choice for treating Rickettsial infections in small animals?
doxycycline
what is the drug of choice for Chlamidophila felis in cats?
doxycyline
why will treatments of tetracyclines often be longer?
because they are bacteriostatic, not bactericidal
chloramphenicol and derivatives
- derivatives of dichloroacetic acid and are potent inhibitors of microbial protein synthesis
- structural difference accounts for differences in toxicity profiles between chloramphenicol and others
- originally obtained from Streptomyces venezulelea
chloramphenicol MOA
binds irreversible to the 50s subunit of bacterial ribosome: inhibits peptidyl transferase which prevents amino acid transfer to the growing polypeptide chain
how does chloramphenicol lead to bone marrow suppression?
inhibits mitochondrial protein synthesis in mammalian bone marrow cells in a dose-dependent manner
are chloramphenicol and derivatives bacteriostatic or bactericidal?
generally bacteriostatic
chloramphenicol spectrum of activity
broad-spectrum effective against many G+ and G- aerobic and anaerobic bacteria
what does chloramphenicol have good activity against?
G+ aerobes including Actinomyces spp, Bacillus anthracis, some strains of MRSP, Gm - aerobes, anaerobes including Bacteroides and Clostridium