Download INHIBITOR of BACTERIAL PROTEIN SYNTHESIS

INHIBITOR of BACTERIAL
PROTEIN SYNTHESIS
BACTERIAL PROTEIN SYNTHESIS
The selectivity for bacterial protein
synthesis is caused by differences in the
structure and function of ribosomes in
prokaryotic versus eukaryotic organisms:
1. Bacteria have 70S ribosomes
(50S and 30S subunites)
Mammalian cell have 80S ribosomes
(60S and 40S subunites)
2. The proteins that initiate and carry out
translation of messenger RNA (mRNA) in
eukaryotic systems are more complex
Bacterial protein synthesis and sites of drug action. The
bacterial ribosome is composed of a 30S subunit and a 50S
subunit. The steps in protein synthesis and translation of
messenger RNA (mRNA) include the binding of aminoacyl
transfer RNA (tRNA) to the ribosome, the formation of a peptide
bond, and translocation. (A) Under normal circumstances, the
nascent peptide is attached to the ribosome at the peptidyl site (P
site), and the next aminoacyl tRNA binds to the acceptor or
aminoacyl site (A site). Tetracyclines block aminoacyl tRNA from
binding to the A site. Aminoglycosides and spectinomycin cause
misreading of the genetic code, which leads to binding of the
wrong aminoacyl tRNA and insertion of the wrong amino acid into
the nascent peptide. (B) Macrolides, chloramphenicol, and
dalfopristin block peptidyl transferase, the enzyme that catalyzes
the formation of a peptide bond between the nascent peptide and
the amino acid attached to the A site. (C) Macrolides and
clindamycin block the translocation step in which the nascent
peptide is transferred from the A site to the P site following the
formation of a new peptide bond.
CLASSIFICATION OF INHIBITORS OF BACTERIAL PROTEIN SYNTHESIS
Drugs That Affect The 30S Ribosomal Subunit
Aminoglycosides
•Gentamicin
•Neomycin
•Streptomycin
Tetracyclines
•Doxycycline
•Minocycline
•Tetracycline
Other Antibiotics
•Spectinomycin
Drugs That Affect The 50s Ribosomal Subunit
Macrolides
Azithromycin (zithromax)
Clarithromycin (biaxin)
Erythromycin
Ketolide
Telithromycin (ketek)
Other Antibiotics
Chloramphenicol
Clindamycin (cleocin)
Quinupristin-dalfopristin (synercid)
Other Bacterial Protein Synthesis Inhibitors
Mupirocin (bactroban)
Linezolid (zyvox)
AMINIGLYCOSIDES CHEMICAL
STRUCTURE
The aminoglycosides
consist of two or more
amino sugars joined
in glycosidic linkage
to a hexose nucleus
which is usually in a
central position
Drugs That Affect The 30S Ribosomal Subunit
Aminoglycosides
PHARMACOKINETIC
• highly polar compounds
• not abosorbed after oral administration
(only parenteral dosage forms im, iv)
• After paranteral administration they are absorbed
well
• limited tissue penetration
(can’t cross BBB, can’t enter the eye)
• GF is the major mode of excretion
(attention in renal insufiency)
• needs monitoring of plasma levels
Drugs That Affect The 30S Ribosomal
Subunit
Aminoglycosides-2
MECHANISM of RESISTANCE
• Plasmid-mediated fromation of inactivating
enzymes
CLINICAL USES
• They are important drugs for the treatment of
serious infections caused by aerobic gr(-)
bacteria
• When used alone they are not reliably effective in
the treatment of gr(+) cocci
• Antibacterial synergy may occur with the
combination of wall synthesis inhibitors
• Streptomycintuberculosis
• Spectinomycingonorrhea (i.m single dose)
SITES OF ACTIVITY OF VARIOUS
PLASMID-MEDIATED ENZYMES
• 20 different enzymes have been detected so
far.Amikacin is less susceptible to these enzymes, and is
effective against many gentamicin-resistant Gramnegative bacilli (Explanation of the lack of crossresistance among various aminoglycosides). Changes in
the ribosomal proteins in resistant bacteria can also
reduce drug binding and antibacterial effectiveness,
particularly for streptomycin. Netilmicin remains effective
against many of these gentamicin-resistant bacteria.
Resistance resulting from reduced penetration of the
drug can be overcome by co-administration of
antibacterials that disrupt cell wall synthesis, such as
penicillins.
SIMPLIFIED DIAGRAM OF GRAMNEGATIVE BACTERIUM
Cell wall
The outer shell is penetrated by porins –channels providing
hydrophilic access to the cytoplasmic membrane-
Drugs That Affect The 30S Ribosomal
Subunit
Aminoglycosides-3
ADVERSE EFFECTS and TOXICITY
Ototoxicity audiotory impairment
vestibular dysfunction
*ototoxicity is proportionate to the plasma level
** ototoxicity may increase with the loop diuretics
*** ototoxicity is irreversible
Nephrotoxicity  Gentamicin, Tobramycin
* generally reversible and at the high doses
Neuromuscular blockade Curare like blockade
*generally reversible use neostigmine
PLASMA CONCENTRATION AFTER
ADMINISTRATION OF GENTAMYCIN
iv AS A SINGLE OR DIVIDED DOSES
TETRACYCLINS
Drugs That Affect The 30S Ribosomal
Subunit
Tetracyclines
PHARMACOKINETIC
• Oral absorption is impaired by foods and
cations (calcium, iron, aluminum)
• Have a wide tissue distribution
• Can cross plasental barrier
• All of them go entero-hepatic cycling
• Eliminated
by
kidneys
except
doxycycline (feces)
Drugs That Affect The 30S Ribosomal
Subunit
Tetracyclines-2
MECHANISM of RESISTANCE
• Plasmid-mediated fromation of inactivating
enzymes
• Development of efflux-pump
CLINICAL USES
1. Primary use: Mycoplasma pneumonia, Chlamydia,
Rickettsia, Vibrio
2. Secondary use: alternative to syphilis
prophylaxis against infections in
bronchitis
in the treatment of acne
Drugs That Affect The 30S Ribosomal
Subunit
Tetracyclines-2
3. Selective uses:
tetracyclineH.pylori infection in the
ulcer
doxycycline inhibits the renal action
of ADH used in the treatment of ADHsecreting tumor
Drugs That Affect The 30S Ribosomal
Subunit
Tetracyclines-3
ADVERSE EFFECTS and TOXICITY
1. Bony structure and teeth  fetal exposure
lead to tooth enamel dysplasi and irregularity in
bone growth
2. Hepatic toxicity  high doses
3. Renal toxicity  exacerbate preexisting renal
dysfunction
4. Photosensitivity  sensitivity to ultra violet
light
5.
Nausea, vomiting, epigastric discomfort, diarrhea
Drugs That Affect The 50s Ribosomal
Subunit
Chloramphenicol
PHARMACOKINETIC
• Very lipophilic (well absorbed from the gut)
• Highly accumulated in the CNS (treatment of
menengitis)
• Metabolized partly glucuronate conjugation
(neonates have low level of glucuronosyl
transferase reduced dose in neonates)
(gray-baby syndrome)
• Kidney excretion, has a short half life.
↓ dose with liver or kidney disease.
Drugs That Affect The 50s Ribosomal
Subunit
Chloramphenicol-2
CLINICAL USES
• Meningococal
and
pneumococal
infections (H. İnfluenzae)
• Also used for the treatment of serious
infections caused by Ricettsia
• Topical use for eye infection
Drugs That Affect The 50s Ribosomal
Subunit
Chloramphenicol-3
ADVERSE EFFECTS and TOXICITY
1. Gastrointestinal discomfort
2. Bone marrow: anemia (reversible)
3. Aplastic anemia: idiosyncratic reaction
(irreversible and fatal)
4. Gray baby sydrome:in neonates with high
doses
cyanosis, decreased red blood cells
and cardiovascular collapse
LINEZOLID
•
•
•
•
A new class of synthetic antimicrobials
Effective against gram positive organisms
Also active against M. Tuberculosis
Binds to the 23S ribosomal RNA of the
50S subunit