INHIBITOR of BACTERIAL PROTEIN SYNTHESIS 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 70 S ribosomes (50 S and 30 S subunites) Mammalian cell have 80 S ribosomes (60 S and 40 S subunites) 2. The proteins that initiate and carry out translation of messenger RNA (m. RNA) in eukaryotic systems are more complex

Bacterial protein synthesis and sites of drug action. The bacterial ribosome is composed of a 30 S subunit and a 50 S subunit. The steps in protein synthesis and translation of messenger RNA (m. RNA) include the binding of aminoacyl transfer RNA (t. RNA) 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 t. RNA binds to the acceptor or aminoacyl site (A site). Tetracyclines block aminoacyl t. RNA from binding to the A site. Aminoglycosides and spectinomycin cause misreading of the genetic code, which leads to binding of the wrong aminoacyl t. RNA 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 30 S Ribosomal Subunit Aminoglycosides • Gentamicin • Neomycin • Streptomycin Tetracyclines • Doxycycline • Minocycline • Tetracycline Other Antibiotics • Spectinomycin Drugs That Affect The 50 s 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 30 S 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 30 S 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 30 S 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 30 S 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 30 S 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 30 S 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 30 S 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 to ultra violet light 5. Nausea, vomiting, epigastric discomfort, diarrhea

Drugs That Affect The 50 s 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 50 s 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 50 s 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 23 S ribosomal RNA of the 50 S subunit