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االسبوع الثاني Microbiology ANTIBACTERIAL DRUGS Importance of antimicrobial therapies is selective toxicity: selective inhibition of the growth of microorganisms without damaging the host. So it should be very toxic to the bacteria, but not/very little toxic to humans. This is done by using the difference between metabolism and structure of the microorganism + the features of the human cell. Major site of action for bacterial drugs: 1. Cell wall 2. Ribosomes 3. Nucleic acid 4. Cell membranes Broad spectrum drugs: are active against several types of organisms, e.g. cephalosporins, aminoglycosides, tetracyclins. Narrow spectrum drugs: are active against one or very few types of microorganisms, e.g. vancomycin for staphylococci and enterococci only. Bactericidal drugs: kills the bacteria Bacteriostatic drugs: inhibits the bacteria’s growth, but doesn’t kill it. Chemoprophylaxis drugs: are used to prevent disease, e.g. penicillin and ampicillin. Used in 3 circumstances: a) Prior to surgery b) In immunocompromised patients c) In people who have been exposed to an organism When choosing a drug, one should be aware of: sufficient therapeutic concentration, appropriate dosage and timing. Antibiotics with bactericidal effect: 1. Penicillin 2. Cephalosporins 3. Aminoglycosied 4. Fluroquinolons Broad spectrum penicillin derivatives for both Gand G+: 1. Ampicillin 2. Amoxicillin 3. Piperacillin 4. Azlocillin 5. Mezlocillin Microbiology Titles Negar Barazandeh Basic Bacteriology, Parasitology, Mycology. 6 of 84 2. Major groups of antibacterial drugs. Mechanism of action of antibacterial drugs. 1. Inhibition of cell wall synthesis: Penicillin Binds to active site of transpeptidase and in this way inhibits peptidoglycan synthesis (which is needed for the cell’s structural support). Exposure to penicillin activates autolytic enzymes that degrade the bacteria. If these autolytic enzymes are not activated, the bacteria are not killed – seen in some strains of Staphylococcus Aureus (said to be tolerant). It kills bacteria when they are growing i.e. when they are synthesizing new peptidoglycans. Penicillins are thus more effective/active during the log phase/exponential phase than during lag phase. Both penicillin and cephalosporin are ß-lactam drugs, meaning an intact ß-lactam ring is needed for activity. Without it, they won’t work Hypersensitivity to penicillin is a growing problem. All penicillin family antibiotics have ß-lactam ring, this is why they are called β-lactam antibiotics. Penicillin passes through channels in the cell wall called porin – then the ßlactam ring binds to and inhibits the transpeptidase enzyme cell wall synthesis gets arrested and the cell dies. So in order to be effective, the β-lactam penicillin must: a) Penetrate the cell layers b) Keep its ß-lactam ring intact c) Bind the transpeptidase The purpose of using ß-lactamase inhibitors in antibacterial therapy is that the combination of ßlactamase inhibitors (e.g. clavulanic acid or sulbactam) with ß-lactamase sensitive penicillins (e.g. amoxicillin or ampicillin) can overcome resistance mediated by many but not all lactamase. Cephalosporins Is structurally same as penicillin – both have ß-lactam ring. Inhibits cross-linking of peptidoglycan. Has a broad range, well tolerated and fever hypersensitivity reactions than penicillin. First generation cephalosporins are mainly active against G+ cocci, while 2nd, 3rd and 4th generation cephalosporins have expanded to also act against G+ rods. Vancomycin Is a glycopeptide – not a ß-lactamase. It inhibits cell wall synthesis in G+ bacteria by blocking transpeptidase. 2. Inhibition of protein synthesis: Aminoglycosides Acts on 30s subunit of bacteria. It inhibits bacterial protein synthesis by binding to 30s subunit, which blocks the initiation complex. No peptide bonds are formed and no polymerases are made. Are a family of bactericidal drugs which include: - Gentamicin - Tobramycin - Streptomycin - Amikacin Tetracyclines Acts on 30s subunit of bacteria. Inhibits bacterial protein synthesis by blocking the binding of aminoacyl t-RNA to the 30s ribosomal subunit. Effective against both G+ and G-. Chloramphenicol Acts on 50s subunit. Inhibits bacterial protein synthesis by blocking peptidyl transferase the enzyme that adds new amino acids to the growing polypeptide. Effective against G+, G- and anaerobes. Erythromycin Acts on 50s subunit Inhibits bacterial protein synthesis by blocking the release of the t-RNA after is has delivered its amino acids to the growing polypeptide. Erythromycin is a member of the macrolides family. Has wide spectrum of activity. Clindamycin Acts in the same way as erythromycin Effective against many anaerobic bacteria