Antimicrobial Drugs PDF

Microbiology/Bacteriology Third year Antimicrobial Drugs Dr Trefa M Abdullah M.Sc. in Medical Microbiology MPhil/Ph.D. in Medical studies/Immuno-oncology Medical School/ Exeter University / UK Lecturer at College of Pharmacy/ Sulaymani University Assistance Professor at the American University Antim...

Microbiology/Bacteriology Third year Antimicrobial Drugs Dr Trefa M Abdullah M.Sc. in Medical Microbiology MPhil/Ph.D. in Medical studies/Immuno-oncology Medical School/ Exeter University / UK Lecturer at College of Pharmacy/ Sulaymani University Assistance Professor at the American University Antimicrobial agent Any chemical or drug used to treat an infectious disease, either by inhibiting or killing the pathogen in vivo. Most microbiologist distinguish two groups of antimicrobial agents used in the treatment of infectious disease: antibiotics, which are natural substances produced by certain groups of microorganisms, and chemotherapeutic agents, which are chemically synthesized. Characteristics of Antibiotics Antibiotics are chemical substances (low-molecular weight substances) that can inhibit the growth of, and even destroy, harmful microorganisms. They are derived from special microorganisms or other living systems. Antibiotics are produced as secondary metabolites by certain groups of microorganisms, especially Streptomyces, Bacillus, and a few molds (Penicillium and Cephalosporium) that are inhabitants of soils on an industrial scale using a fermentation process. Antibiotic/Antimicrobial Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms Chemotherapy The use of drugs to treat a disease Selective toxicity: A drug that kills harmful microbes without damaging the host. Antibiotics may have acidal (killing) effector static (inhibitory) effect on a range of microbes. The range of bacteria or other microorganisms that is affected by a certain antibiotic is expressed as its spectrum of action. Antibiotics effective against procaryotes that kill or inhibit a wide range of Gram-positive and Gram-negative bacteria are said to be broad spectrum. If effective mainly against Gram-positive or Gram-negative bacteria, they are narrow spectrum. If effective against a single organism or disease, they are referred to as limited spectrum. Used to kill or inhibit the growth of bacteria Classified as bactericidal or bacteriostatic Kill bacteria directly Prevent cell division Classified by target specificity: Narrow-spectrum vs Broad range Bacteria have their own enzymes for – – – – – Cell wall formation Protein synthesis DNA replication RNA synthesis Synthesis of essential metabolites Mechanisms of Antimicrobial Action Inhibition of Cell Wall Synthesis (most common mechanism) Inhibition of Protein Synthesis Alteration of Cell Membranes. Inhibition of Nucleic Acid Synthesis. Antimetabolite Activity. The Penicillin Mode of action The targets of the penicillins are enzymes (transpeptidase) which called penicillin binding proteins (PBPs) ,the transpeptidase is involved in synthesis of the cell wall. Penicillin attacks bacterial cells by inactivating this enzyme which is essential for bacterial growth(peptidoglycan transpeptidase catalyses the cross-linking of the peptidoglycan, which forms the cell wall of the bacteria). The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. Therefore, the penicillin can safely disrupt the bacterial cell wall biosynthesis without harming existing cells in the body. The penicillin stops the growth of the bacterial cell wall, causing the pressure inside the cell to rise considerably until the cell lyses and thus the cell is destroyed(in other words, the antibiotic causes cytolysis or death due to osmotic pressure). Classification 1-Natural penicillins (Narrow spectrum –penicillinase (lactamase) sensitive) Natural penicillins, including penicillin G& penicillin V. They are active against non β-lactamase– producing gram-positive cocci (Pneumococci, Staphylococci, Streptococci), few gram-negative cocci (meningococci and gonococci), gram-positive bacilli (Bacillus anthracis, Bacillus diphtheriae), anaerobes (Clostridium perfringens, C. tetani). They are considered narrow spectrum since they are not effective against Gram-negative rods. The natural penicillins are very susceptible to inactivation by beta-lactamases. Penicillin G Penicillin V 2-Narrow spectrum –penicillinase (lactamase) resistant(Anti-Staphylococcal Penicillins) These drugs were created in response to the problem in the 1950’s, staphylococcal infections in hospitals were resistant to penicillin due to production of beta-lactamase. Anti-Staphylococcal Penicillins are semi-synthetic, and have big bulky sidechains to protect the beta-lactam from cleavage by the beta lactamases. This group of penicillin drugs includes: a-Methicillin(Poor oral availability), (Flucloxacillin). b-Nafcillin. (Good oral availability) Penicillinase (b Lactamase) -Broad spectrum –penicillinase (lactamase) sensitive(Aminopenicillins) Ampicillin, amoxicillin. The aminopenicillins have a wider range of activity than natural or antistaphylococcal penicillins. However, they lack the bulky side groups and are susceptible to inactivation by beta-lactamases. Aminopenicillins have additional hydrophilic groups, allowing the drug to penetrate Gram-negative bacteria via the porins. Advantages of aminopenicillins include higher oral absorption, higher serum levels, and longer half-lives. Aminopenicillins are resistant to gastric acids so can be administered orally. Spectrum: Aminopenicillins are similar to penicillin G in their activity against Gram-positive organisms but are slightly weaker than the latter. Aminopenicillins are more active against enterococci and Listeria monocytogenes compared to penicillin G. Gram-negative spectrum includes Haemophilus influenzae, Salmonella, Shigella, Escherichia coli, and Proteus. 4-Extended spectrum –penicillinase (lactamase) sensitive(Anti-pseudomonal penicillins) Extended-spectrum penicillins (also called anti-pseudomonas) include both carboxypenicillins (carbenicillin). Antipseudomonal penicillins are similar to the aminopenicillins in structure but have either a carboxyl group or instead of an amine. In general, the antipseudomonal penicillins have greater activity than other penicillins against gram-negative bacteria (especially Pseudomonas and Proteus) due to enhanced penetration through the cell wall of these bacteria. The major advantage of carboxypenicillins is their activity against Pseudomonas aeruginosa(one of the major pathogens responsible for nosocomial pneumonia) and certain indole-positive Proteus species that are resistant to aminopenicillins. Beta-lactamase inhibitors clavulanic acid, tazobactam, sulbactam-poor antimicrobial activity on their own. They are potent inhibitors of many bacterial betalactamases and can protect hydrolyz able penicillins from inactivation by these enzymes, but poor activity for chromosomal cephalosporinases.they are beta-lactam structures, beta-lactamases inhibitor because they are β–lactam analogue. Clavulanic acid is not an antibiotic. It is a beta-lactamase inhibitor sometimes combined with semisynthetic beta lactam antibiotics to overcome resistance in bacteria that produce beta-lactamase enzymes, which otherwise inactivate the antibiotic, clavulanic acid is an irreversible, "suicide" inhibitor of beta-lactamase. Most commonly it is combined with amoxicillin is clavamoxor augmentin.(trade name) The Cephalosporins Cephalosporins are structurally and pharmacologically related to the penicillins. They are often used as penicillin substitutes against Gram-negative bacteria and in surgical prophylaxis. They are subject to degradation by some bacterial beta-lactamases, but they tend to be resistant to beta-lactamases from S. aureus. Cephalosporin(Bactericidal) prevents cell wall synthesis by binding to enzymes called penicillin binding proteins (PBPs). These enzymes are essential for the synthesis of the bacterial cell wall. Cephalosporin's are derived from cephalosporin C ( natural cephalosporin's) which is an acidstable molecule with antibacterial activity. The tetracycline core structure. The tetracyclines are broad-spectrum antibiotics with a wide range of activity against both Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa is less sensitive but is generally susceptible to tetracycline concentrations that are obtainable in the bladder. The tetracyclines are bacteriostatic compounds. They inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the ribosome (act on 30S ribosomal subunit). Tetracycline is absorbed well orally. Aminoglycosides Aminoglycosides are a group of drugs sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. They are potent bactericidal antibiotics, including several natural and semisynthetic compounds used to treat bacterial diseases. They are particularly active against aerobic, gram-negative bacteria and act synergistically against certain gram-positive organisms. Neomycin, isolated from Streptomyces, had better activity than streptomycin against aerobic gram-negative bacilli but, because of its toxicity, could not safely be used systemically. Mechanism of Action The aminoglycosides act directly on the bacterial ribosome to inhibit the initiation of protein synthesis and to interfere with the fidelity of translation of the genetic message. They bind to the 30S ribosomal subunit to form a complex that cannot initiate proper amino acid polymerization. Other Inhibitors of Cell Wall Synthesis Polypeptide antibiotics Bacitracin Topical application, cell wall synthesis inhibitors Against gram-positives, normally in bacterium, bactoprenol is the lipid membrane carrier that transports building blocks cross the cytoplasmic membrane Vancomycin Glycopeptide antibiotic prevents cross-linking of peptidoglycan cell wall. Important "last line" against antibiotic-resistant S. aureus