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Antimicrobial agents : mechanisms of action and resistance

İ. Çağatay Acuner M.D., Clinical Microbiologist, Associate Professor Department of Microbiology Faculty of Medicine , Yeditepe University , Istanbul cagatay.acuner@yeditepe.edu.tr. Antimicrobial agents : mechanisms of action and resistance.

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Antimicrobial agents : mechanisms of action and resistance

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  1. İ. Çağatay Acuner M.D., Clinical Microbiologist, Associate Professor Department of MicrobiologyFaculty of Medicine, Yeditepe University, Istanbul cagatay.acuner@yeditepe.edu.tr Antimicrobial agents:mechanisms of action and resistance

  2. Global Sorun: Antibiyotik Direnci (WHO, 2011, Dünya Sağlık Günü Teması)

  3. Antibiotic resistance challenge

  4. Antibiotic resistance challenge

  5. Antibiotic resistance challenge

  6. Temel Terminoloji • Antibiyotik: Canlı organizmalardan elde edilmiş (geçmişte; günümüzde sentetik dahil) ve (genellikle) bakteriyel infeksiyonların tedavisinde kullanılan maddelerdir. • Antimikrobiyal: Bakteri, mantar, protozoon, virus gibi mikroorganizmaların üremesini durduran (statik) veya öldüren (sidal) maddelerdir. (Dezenfektan; cansız nesnelere veya vücut-dışı kullanılan) • Antibakteriyel, antiviral, antifungal, antiparazitik

  7. Temel Terminoloji • Duyarlı: İnfeksiyon bölgesi için önerilen doz kullanıldığında, antimikrobiyal ajanın genellikle erişilebilir konsantrasyonları ile bakteriyel izolatlar inhibe edilir. • Dirençli (doğal dirençli, kazanılmış dirençli): İnfeksiyon bölgesi için önerilen doz kullanıldığında, antimikrobiyal ajanın genellikle erişilebilir konsantrasyonları ile bakteriyel izolatlar inhibe edilmez; ve/veya; inhibe olduğu zon çapı veya MİK değeri, spesifik direnç mekanizmalarının olabileceği kırılma-noktası aralığına (örn. beta-laktamazlar) düşer ve ajanın bakteriyel izolata karşı etkinliği klinik olarak tedavi araştırmalarında güvenilir olarak gösterilememiştir. • Orta duyarlı: Ajanın genellikle erişebildiği kan ve doku MİK düzeylerine karşı duyarlı izolatlara kıyasla klinik yanıtın daha az olduğu bakteriyel izolatlar için kullanılır. Droğun fizyolojik olarak konsantre olduğu kompartmanlarda etkili olabilir (örn. idrarda kinolon ve beta-laktamlar). Ayrıca, dar farmakotoksisite marjini olan droglar için, küçük, kontrol edilemeyen teknik faktörlerin, sonuç yorumunda majör uyumsuzluğa neden olmaması için bir tampon aralığıdır. • Çoklu-dirençli (MDR): ≥ x2 kimyasal sınıf; farklı tanımlamalar var! • Aşırı-dirençli (XDR): XDR-TB (R ≥INH+RMP+FQ+AG) • Pan-drog dirençli (PDR): tartışmalı tanım önerileri var!

  8. Temel Terminoloji

  9. Outline • General features of antimicrobials • Classification of antimicrobialsbased on mechanisms of effectandresistancemechanisms • Inhibition of cell-wallsynthesis • Increase in cell-membranepermeability • Inhibition of protein synthesis • Inhibition of nucleicacidsynthesis • Antimetabolites

  10. Terminology

  11. Past, Present, and Future • Topical antisepticswereineffective against systemic bacterial infections. • In 1935, the dye prontosil was shown to protect mice against systemic streptococcal infection and to be curative in patients suffering from such infections. • It was soon found that prontosil was cleaved in the body to release p-aminobenzenesulfonamide (sulfanilamide), which was shown to have antibacterial activity. • This first "sulfa" drug started a new era in medicine; chemotherapy

  12. Past, Present, and Future • Compounds produced by microorganisms (antibiotics) were discovered that inhibit the growth of other microorganisms • Alexander Fleming was the first to realize the mold Penicillium prevented the multiplication of staphylococci. • Streptomycin and the tetracyclines were developed in the 1940s and 1950s • Aminoglycosides, semisynthetic penicillins, cephalosporins, quinolones, and other antimicrobials followed. • All these antibacterial agents greatly increased the range of infectious diseases that could be prevented or cured. • Although the development of new antibacterial antibiotics has lagged in recent years, some new classes of agents have been introduced:ketolides (e.g., telithromycin), glycylcyclines (tigecycline), lipopeptides (daptomycin), streptogramins (quinupristin-dalfopristin), and oxazolidinones (linezolid). • Unfortunately, with the introduction of new chemotherapeutic agents, bacteria have shown a remarkable ability to develop resistance. • Thus antibiotic therapy is only one weapon, against infectious diseases. • As resistance to antibiotics is not predictable, physicians must rely on local surveillance (epidemiological) data and guidelines for the initial selection of empirical therapy.

  13. Antibiotics • Toxic for the microorganismal agent • In host, • non-toxic, or • tolerable toxicity • The effects of this selective toxicity in microorganism; • Inhibition of growth (bacteriostatic), or • Death (bactericidal)

  14. Antibiotics • Bacteriostaticeffect is sufficient in most of thepatients • Afterinhibition of growth, immunesystemeliminatesthebacteria • However; • Inimmunodeficientpatients, or • Inseriousinfectionssuch as, endocarditis, meningitis, etc. bactericidaleffect is required

  15. Antibiotics • Usually, the effect of antibiotics on bacteria occur by more than one mechanism • An antimicrobial agent that distrupts the cell-wall synthesis may also distrupt the protein or nucleic acid synthesis at certain concentration level • However, usually, one of these mechanisms is more important than others

  16. Mechanisms of antimicrobial effect • Inhibition of cell-wall synthesis • Increase in cell-membrane permeability • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis • Antimetabolites

  17. Cell-wall in bacteria

  18. Cell-wall in bacteria

  19. Antimicrobials that act by cell-wall inhibition • Beta-lactams; • Penicillins; • Natural penicillins; penicillin G, penicillin V • Aminopenicillins; ampicillin, amoxicillin • Anti-stafilococcal penicillins; methicillin, nafcillin, oxacillin • Anti-pseudomonal penicillins; carbenicillin, ticarcillin, ureidopenicillins ( piperacillin) • β-Lactam with β-lactamase inhibitor (combination) • ampicillin-sulbactam, • amoxicillin-clavulanate, • ticarcillin-clavulanate, • piperacillin-tazobactam • Cephalosporins and Cephamycins; • First generation (narrow spectrum) ; cephalexin, cephalothin, cefazolin, cephapirin, cephradine • Second generation (expanded-spectrum); cefaclor, cefuroxime • Expanded-spectrum cephamycins ; cefotetan, cefoxitin • Third generation (broad spectrum); cefixime, cefotaxime, ceftriaxone, ceftazidime, cefoperazon • Fourth generation (extended spectrum); cefepime, cefpirome • Monobactams; aztreonam • Carbapenems; imipenem, meropenem, ertapenem

  20. Antimicrobials that act by cell-wall inhibition • Glycopeptides; vancomycin, teicoplanin • Bactericidal for bacteria in exponential growth • Effective on Gr (+)s • Some Gr (+)s are resistant intrinsically • Lactobacillus • Pediococcus • Leuconostoc • Phosfomycin • inactivates the enzyme UDP-N-actetylglucosamine-3-enolpyruvyltransferase • NAM production from NAG is blocked in the cytoplasm and cell-wall synthesis is impaired • Ethionamide • Bacitracin • Isoniazid

  21. Antimicrobials that act by cell-wall inhibition • Cycloserine; • Analogue of D-alanine • D-alanine-D-alanine bond is prevented; so, production of cell-wall precursor is avoided • Highly toxic • Only for use in the treatment of resistant M. tuberculosis infections

  22. Antimicrobials that act by cell-wall inhibition • Cell-wall synthesis is organized by; • Transpeptidase, • Carboxypeptidase, • Endopeptidase, • These enzymes can also bind beta-lactam antibiotics, so; • also called PBPs (penicillin-binding proteins) • In a bacterium that grows; • Antibiotics are bound to PBPs • Otolytic enyzmes are released • Cell-wall cannot be produced

  23. Antimicrobials that act by cell-wall inhibition • Numerous PBPs can be found in a bacterium • These enzymes are classified as PBP-1, PBP-2, PBP-3, etc., respectively, based on the order of their molecular weights • If a PBP with a mid-range weight is discovered later on, it is named as PBP-1a, PBP-1b, etc.

  24. Antimicrobials that act by cell-wall inhibition • Affinity to PBPs differs among beta-lactam antibiotics • Therefore, efficacy of distinct beta-lactam antibiotics on distinct bacteria are different • Most significant effect of beta-lactams are on transpeptidases • Usually, beta-lactams with an affinity to larger PBP molecules are more potent

  25. Antimicrobials that act by inhibition of protein synthesis • Aminoglycosides (30S); • streptomycin, kanamycin, gentamicin, tobramycin, amikacin • Tetracyclines (30S); • tetracycline, doxycycline, minocycline • Macrolides (50S); • erythromycin, azithromycin, clarithromycin, spiramycin, roxithromycin • Ketolides (50S); • telithromycin • Lincosamide (50S); • clindamycin, lincomycin • Chloramphenicol (50S) • Streptogramins (50S); • quinupristin-dalfopristin • Oxazolidinone (50S); • linezolid • Fusidic acid

  26. Aminoglycosides • By binding to bacterial ribosomes; • inhibition of protein synthesis • mismatch reads in mRNA codons; incorporation of wrong aa’s in polypeptides; non-functional proteins • mis-reading as a stop codon; termination before a completed synthesis of a protein

  27. Aminoglycosides • They pass bacterial membrane in two steps • In the first step, energy is not required • In the second step, energy is required • Their effect is bactericidal • Inhibiton of protein synthesis, and • Disruption of cytoplasmic membrane structure

  28. Aminoglycosides • Active transport with energy and oxygen is inhibited by; • cations like Ca ve Mg, • in anaerobic conditions, • in low pH, • in high osmolarity, • Therefore, activity is decreased; • in anaerobic conditions of abcesses, or • acidic and hyperosmolar environment of urine

  29. Tetracyclines • in Gr (-) bacteria, they can enter through the porin chanells in cell-wall by passive diffusion • bind reversibly to the 30S ribosomal subunits, thus block the binding of aminoacyl-transfer RNA (tRNA) to the 30S ribosome-mRNA complex • peptide chain is not elongated • Bacteriostatic • However, aluminum, calcium, magnesium, iron in the nutritional uptake, • causes chelation with and inactivates tetracycline

  30. Chloramphenicol • by binding reversibly to the peptidyl transferase component of the 50S ribosomal subunit, blocks peptide elongation • Bacteriostatic

  31. Macrolides • by their reversible binding to the 23S rRNA of the 50S ribosomal subunit, which blocks polypeptide elongation (through blocking tRNA molecule) • Bacteriostatic

  32. Lincosamides, Streptogramins: • blocks protein elongation by binding to the 50S ribosome (same site withmacrolides) Mupirocin: • inhibitsisoleucine t-RNA synthetasethatintegratesisoleucinandtRNA • inhibitsbacterialtRNAsynthesis, and • protein synthesis Fucidicacid: • acts as a bacterial protein synthesis inhibitor by preventing the turnover of elongation factor G (EF-G) from the ribosome

  33. Antimicrobials that act by inhibition of nucleic acid synthesis • Quinolones • nalidixic acid • fluoroquinolones • ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, pefloxacin, levofloxacin, moxifloxacin • Rifampin • Metronidazole

  34. Quinolones • Mechanism of effect; • inhibits the enzymes (topoisomerase type II (gyrase) or topoisomerase type IV) that have functions in; • DNA replication • DNA recombination • DNA repair • Therefore, inhibits nucleic acid synthesis • The DNA gyrase-A subunit is the primary quinolone target in gram-negative bacteria, whereas topoisomerase type IV is the primary target in gram-positive bacteria

  35. Quinolones • Bactericidal • There may be other mechanisms effective • The differences in efficacy of distinct quinolones caused by differences in binding to enyzme-DNA complexes

  36. Rifampicin (Rifampin) • binds to DNA-dependent RNA polymerase and inhibits the initiation of RNA synthesis • Bactericidal • Similar enzymes in mammalian cells are less sensitive to rifampicins

  37. Antimetabolites • Sulfonamides • Trimethoprim • Dapsone (sulfons)

  38. Antimicrobials that act by an increase in cell-membrane permeability • Polymyxins and Colistin • act like cationic detergents and damagecytoplasmic membrane by interacting with the phospholipids and incresing the permeability • also damage the cell-wall lipopolisaccarides in Gr (-) bacteria

  39. Mechanisms of action

  40. Mechanisms of action

  41. Mechanisms of action

  42. Antimicrobial consumption

  43. Antimicrobial spectrum • Range of activity of an antimicrobialagainstbacteria • Broadspectrum: inhibits a widevariety of gram-positiveand gram-negativebacteria • Narrowspectrum: activeagainst a limitedvariety of bacteria

  44. Antimicrobial spectrum

  45. Penicillins

  46. Cephalosporins and Cephamycins

  47. Other beta-lactams

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