Antibiotics Lecture Notes PDF

Antibiotics PROF.DR.BAYDAA HAMEED ABDULLAH  Antibiotic & Antimicrobial agent Antibiotic: is a product produced by a microorganism or a similar substance with molecular weight 250-5000 Dalton produced wholly or partially by chemical synthesis, which in low concentrations, inhibits the grow...

Antibiotics PROF.DR.BAYDAA HAMEED ABDULLAH  Antibiotic & Antimicrobial agent Antibiotic: is a product produced by a microorganism or a similar substance with molecular weight 250-5000 Dalton produced wholly or partially by chemical synthesis, which in low concentrations, inhibits the growth of other microorganisms. Or is a chemical substance produced by various species of microorganisms that is capable in small concentrations of inhibiting the growth of other microorganisms. Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms Production of antibiotics The production of antibiotics has been widespread since the pioneering efforts of Florey and Chain in 1938. The importance of antibiotics to medicine has led to much research into their discovery and production: 1- Actinomycetes & Streptomyces which produce 80% of antibiotics like streptomycin, tetracycline, erythromycin. 2- Fungi like penicillium & cephalosporium which produce Ampicillin, cephalothin. 3- Bacillus like Bacillus Polymyxa which produce polypeptide like polymyxin & colistin.  Antibiotics Actions ▪Bactericidal Kills bacteria, reduces bacterial load ▪Bacteriostatic ✓Inhibit growth and reproduction of bacteria ▪All antibiotics require the immune system to work properly ▪Bactericidal appropriate in poor immunity ▪Bacteriostatic require intact immune system Mechanisms of antibacterial action There are five main mechanisms by which antibacterial agents act. ❖1-Inhibition of cell wall synthesis ❖2-Inhibition to the cell membrane ❖3-Inhibition of protein synthesis ❖4-Interference with metabolism process ❖5-Inhibithion the synthesis of nucleic acids (DNA & RNA) 1- Inhibition of cell wall synthesis (Bactericidal agents) Bacterial cell wall consist from a protective peptidoglycan layer which is a polymer of N- acetylmuramic acid (NAM) & N-acetylglucosamine (NAG). There are two important enzymes working in this place Autolysine: which break the cross link of peptides Transpeptidase: Also called (penicillin binding proteins PBPs) cross link the peptidase (opposite action ) 1- Inhibition of cell wall synthesis 1- The penicillins and cephalosporins, as well as other beta-lactam antibiotics ,they act by inhibiting transpeptidase enzyme.thus the bacteria will loss the integrity of bacterial cell wall , Leak its cellular component and Bacterial cell perish. Usually they attack the D-alanyl-D-alanine (D-Ala-D-Ala) groups found at the terminus of the pentapeptide in most newly synthesized peptidoglycan monomers. Binding of the drug to the transpeptidase ( penicillin binding protein-BPB) ties up the enzyme and prevents it from reforming the peptide cross-links between the rows and layers of new peptidoglycan monomers are added during bacterial cell growth 1- Inhibition of cell wall synthesis 2-The Vancomycin : Bacteriocidal , stopped peptidoglycan elongation. effective against many gram-positive bacteria; used for resistant infections.Useful in treatment of Staphylococcus aureus 3- Cycloserine – inhibits the formation of the basic peptidoglycan subunits 4-Bacitracin Disrupts the bacterial cell wall and is effective against gram-positive bacteria Used topically (skin, mucous membranes, eyes) and as a feed additive Toxic to kidneys 2-Inhibition of Cell Membrane Inhibitors of cell membrane function. Cell membrane is important barriers that regulate the intra- and extracellular flow of substances. A disruption or damage to this structure could result in leakage of important solutes essential for the cell’s survival. Because of high similarity of this structure in both eukaryotic and prokaryotic cells, the action of this class of antibiotic are often poorly selective and can be toxic for the mammalian host(systemic use ). Most clinical usage is topical applications. Examples: polymixin B and colistin ◦ Works by attacking the cell membrane of bacteria used as an ointment or wet dressing Often combined with neomycin and bacitracin (triple ABX ointment) 3- Inhibition of protein synthesis Inhibitors of protein synthesis. Protein synthesis is an essential process necessary for the multiplication and survival of all bacterial cells since all enzymes and most cellular structures are made of proteins. Several types of antibacterial agents target bacterial protein synthesis by binding to either the 30s subunit or 50s subunit of the ribosomes. This will cause disruption the normal bacterial cellular metabolism, and leads to the death of the organism or the inhibition of its growth and multiplication. So the process either will be bactericidal or bacteriostatic 3- Groups causes inhibition of protein synthesis 1- Aminoglycosides group : Are a specialized group of antibiotics with a broad spectrum of activity (BACTERIOCIDAL ), used for gram-negative bacteria and Interfere with protein production ex: gentamicin, neomycin, amikacin, tobramycin, and streptomycin. The primary mechanism of action of aminoglycosides is: The drug bound to the prokaryotic ribosome at the 16S ribosomal RNA (rRNA) site located in the small (30S) subunit of the ribosome Then Binding of the aminoglycoside to the A site for aminoacyl–tRNA inhibits the translation process by causing misreading and/or hindering the translocation step. attachment at the A site suggests that aminoglycosides block transition during the peptide bond–forming translocation stop elongation of the nest protein chain 3- Inhibition of protein synthesis 2- Tetracyclines bacteriostatic antibiotics with a broad spectrum of activity, including rickettsial agents ex: tetracycline, oxytetracycline, chlortetracycline, doxycycline, and minocycline inhibit protein synthesis at this ribosomal level due to disruption of codon– anticodon interactions between tRNA and mRNA in which binding of aminoacyl–tRNA to the ribosomal acceptor site is prevented 3-Inhibition of protein synthesis By Acting on 50S Ribosome site 1- Chloramphenicol : Is a broad-spectrum (bacteriostatic) antibiotic that penetrates tissues and fluids well (including the eyes and CNS :central nerves system ) Binds peptidyl transferase component of 50S ribosome, blocking peptide elongation 2- Clindamycin : Narrow spectrum. Binds 50S ribosome, blocks peptide elongation; Inhibits peptidyl transferase by interfering with binding of amino acid-acyl-tRNA complex 3- inhibition of protein synthesis 3- Macrolides --->bacteriostatic. Reversibly bind to 50s subunit ribosome, and block peptide elongation Macrolides block the approach to the exit tunnel for elongating peptides and thus prevent polypeptide translation, causing premature release of peptidyl–tRNA intermediates Macrolides also block assembly of 50S subunits by their interaction with the 23S rRNA Macrolides such as erythromycin, clarithromycin, and azithromycin. 3- inhibition of protein synthesis Other antibiotics inhibit protein synthesis by interfering with 50s subunit Azolides, Lincosamides, Ketolides, and Streptogramins their mechanism of action against the 50S subunit of the bacterial ribosomes. Lincosamides, however, inhibit the initiation of peptide chain formation 3- inhibition of protein synthesis Nitrofurantoin: inhibit protein synthesis. At the same time, nitrofurans, including nitrofurantoin, have specific interactions with ribosome sites such of the 30S subunit, which disrupts codon– anticodon interactions and thereby prevents mRNA translation mRNAs for inducible enzymes ex : Nitrofurans : Are broad-spectrum antimicrobial agents that include furazolidone, nitrofurazone, and nitrofurantoin Used to treat wounds (topically) and urinary tract infections 4-Interference with metabolism process Sulfonamides : Are broad-spectrum bateceriostatic antibiotics that inhibit the synthesis of folic acid (needed for the growth of many bacteria) Some are designed to stay in the GI tract (enteric forms); some are absorbed by the GI tract and penetrate tissues (systemic forms) Bactericidal when potentiated with trimethoprim Ex: include sulfadiazine/trimethoprim , sulfadimethoxine, 5-Inhibithion the synthesis of nucleic acids (DNA & RNA) Acting on DNA (Bactericidal ) 1- Fluoroquinolones ◦ Are antimicrobial agents with fluorine bound to the quinolone base, which increases the drug’s potency, spectrum of activity, and absorption.they Are broad-spectrum antibiotics (gram + and gram -). Ex: include enrofloxacin, ciprofloxacin, orbifloxacin, difloxacin, marbofloxacin, and sarafloxacin Quinolones Inhibit DNA gyrases required for supercoiling of DNA; bind to alpha subunit 5-Inhibithion the synthesis of nucleic acids (DNA & RNA) Rifampin : Disrupts RNA synthesis ◦ Is broad-spectrum; used in conjunction with other antibiotics (usually erythromycin) Rifampin, like other rifamycins, acts by binding to the β subunit of the RNA polymerase and blocks the extension of the nascent RNA chain after the first or second condensation step Thank you