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Protein Synthesis Inhibitors
Tetracyclines
Macrolides
Chloramphenicol
Aminoglycosides
Clindamycin
Streptogramins
Alan M. Reynared, Ph.D.
QUICK REVIEW - Protein Synthesis
Tetracyclines - Structure
Excretion
R1 R2 R3
tetracycline (Achromycin)
H OH CH3
chlortetracycline (Aureomycin)
H OH CH3
oxytetracycline (Terramycin)
OH OH CH3
demethylchlortetracycline (Declomycin)
H OH H
doxycycline (Vibramycin)
minocycline (Minocin)
OH
H
CH3
H
R4 mg/hr
H
65
Cl
32
H
90
Cl
35
H
H
16
H N(CH3) 9
Tetracyclines - Uses
Gram- Bacteria
 Helicobacter pylori (duodenal ulcer)
 Borrelia recurrentis (Lyme disease, relapsing fever)
Other Organisms
 Mycoplasma pneumoniae
 acne
Tetracycline - Mechanism
 Inhibits protein synthesis
 Static
 Chelates divalent cations -- Ca++, Mg++
Tetracycline - Adverse Effects
 headache, nausea, vomiting
 discoloration of bones and teeth
 photosensitivity
 liver damage
 superinfection
Superinfection
A new infection appearing during treatment
for a primary infection
The organism will be resistant to the antibiotic
used for the primary infection
Organisms causing superinfection
Staphylococcus aureus - enterocolitis
Candida albicans - vagina, mouth
Clostridium difficile - pseudomembranous colitis
Risk factors
in hospital > 6 days
6 > age > 60
broad spectrum antibiotic
Tetracylines
 Administration
Oral administration but interference by
food, Ca++, Mg++
 Excretion
renal, fecal enterohepatic
Chloramphenicol - structure/features
Features
 Broad Spectrum
 Inexpensive
 Oral administration
 Virtually non-toxic
Chloramphenicol - uses/toxicity
Uses
 Haemophilus influenzae (meningitis)
 Typhus
 Rocky Mountain Spotted Fever
 eye infections
Adverse Effects
 superinfection
 aplastic anemia
Chloramphenicol - mechanism
 Inhibits protein synthesis
 Static
Macrolides - structure / names
erythromycin
azithromycin
clarithromycin
Macrolides - uses
whooping cough
pharyngitis
Community-acquired pneumonia
Penicillin-allergic patients
staphylococcus
streptococcus
pneumococcus
Macrolides - mechanism
 Inhibits protein synthesis
 Static
Macrolides - toxicity / drug interactions
Toxicity
 nausea, vomiting, diarrhea
 cholestatic hepatitis (esp. estolate)
Drug Interactions
 inhibit P450 system
Macrolides
Administration
 erythromycin destroyed by gastric acid
- enteric coated tablets
- erythromycin stearate
- erythromycin estolate
 food decreases absorption of all macrolides
Aminoglycosides - structure / names
streptomycin
kanamycin
neomycin
paromomycin
gentamicin
tobramycin
netilmicin
amikacin
spectinomycin
Aminoglycosides - uses
Amikacin
 serious Gram-negative infections
 endocarditis (+ a penicillin or cephalosporin)
Streptomycin
 plague (Yersinia pestis)
 tuleremia (Francisella tulerensis)
 tuberculosis (Mycobacterium tuberculosis)
Aminoglycosides - mechanism
 inhibits protein synthesis
 ribosomal binding is very tight
 cidal
 at high doses  bacterial cell permeability
Aminglycosides - adverse effects
- deafness
- vertigo
- kidney damage
Aminoglycosides - spectinomycin
Use
Reserve drug for gonorrhea
Clindamycin
USES
 Staphylococcus aureus
 Streptococcus pyogenes
 Bacteroides fragilis
 Clostridium tetani
Clindamycin - mechanism
 Inhibits protein synthesis
 static
Clindamycin - adverse effects
superinfection
pseudomembranous colitis
(ulcerative colitis)
Clostridium difficile
Streptogramins
Synercid
 synergistic combination
quinupristin
dalfopristin
 activity against
staphylococci
streptococci
vancomycin-resistant enterococci (VRE)
Drug Resistance
Types of resistance
chromosomal
plasmid-mediated
Mechanisms of resistance
enzymatic destruction of drug
altered target of drug
decreased influx of drug
increased efflux of drug
Drug Resistance
1955 - epidemic of dysentary in Tokyo
Multiple Drug Resistance
tetracycline
10-8
10-8
chloramphenicol
10-8
sulfisoxazole
10-8
streptomycin
all four
10-32
Transmissible Drug Resistance
patient excreting MDR S. dysenteriae and E. coli
Drug Resistance
Bacterial Conjugation
Drug Resistance
Plasmid specifying resistance to 2 antibiotics
Drug Resistance
MDR spread rapidly all over the world
Drug Resistance
Increase in resistance
with increased
production of antibiotics
Drug Resistance - specific antibiotics
penicillin
-lactamase
altered penicillin-binding protein
aminoglycosides
acetylation
AcCoA + AG
phosphorylation
ATP + AG
adenylylation
ATP + AG
AcAG + CoA
P-Ag + ADP
AMP-Ag + PPi
Drug Resistance - specific antibiotics
chloramphenicol
acetylation
AcCoA + CM
erythromycin
altered ribosome
tetracycline
active efflux of drug
AcCM + CoA
Drug Resistance - aminoglycosides
Sulfonamides
Gerhard Domagk, 1895 - 1964
V.P., I. G. Farbenindustrie