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