Protein Synthesis Inhibitors
Tetracyclines Macrolides
Chloramphenicol Aminoglycosides
Clindamycin Streptogramins
Alan M. Reynared, Ph.D.
QUICK REVIEW - Protein Synthesis
Tetracyclines - Structure
Excretion R1 R2 R3 R4 mg/hr
tetracycline (Achromycin) H OH CH3 H 65chlortetracycline (Aureomycin) H OH CH3 Cl 32oxytetracycline (Terramycin) OH OH CH3 H 90demethylchlortetracycline (Declomycin) H OH H Cl 35 doxycycline (Vibramycin) OH CH3 H H 16minocycline (Minocin) H H 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 antibioticused for the primary infection
Organisms causing superinfection Staphylococcus aureus - enterocolitis Candida albicans - vagina, mouth Clostridium difficile - pseudomembranous colitis
Risk factorsin hospital > 6 days6 > age > 60broad 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
erythromycinazithromycinclarithromycin
Macrolides - uses
whooping coughpharyngitisCommunity-acquired pneumoniaPenicillin-allergic patients
staphylococcusstreptococcuspneumococcus
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
streptomycinstreptomycin gentamicingentamicinkanamycin tobramycinneomycin netilmicinparomomycin amikacinamikacin
spectinomycinspectinomycin
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 combinationquinupristindalfopristin
activity againststaphylococcistreptococcivancomycin-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 Resistance1955 - epidemic of dysentary in Tokyo
Multiple Drug Resistance
streptomycin 10-8
tetracycline 10-8
chloramphenicol 10-8
sulfisoxazole 10-8
all four 10-32
Transmissible Drug Resistance
patient excreting MDR S. dysenteriae and E. coli
Drug ResistanceBacterial Conjugation
Drug ResistancePlasmid specifying resistance to 2 antibiotics
Drug ResistanceMDR spread rapidly all over the world
Drug ResistanceIncrease in resistancewith increasedproduction of antibiotics
Drug Resistance - specific antibiotics
penicillin
-lactamasealtered penicillin-binding protein
aminoglycosidesacetylation
AcCoA + AG AcAG + CoA
phosphorylationATP + AG P-Ag + ADP
adenylylation
ATP + AG AMP-Ag + PPi
Drug Resistance - specific antibiotics
chloramphenicolacetylation
AcCoA + CM AcCM + CoA
erythromycinaltered ribosome
tetracyclineactive efflux of drug
Drug Resistance - aminoglycosides
Sulfonamides
Gerhard Domagk, 1895 - 1964V.P., I. G. Farbenindustrie