رئوس مطالب

2. رئوس مطالب تاريخچه آنتی بيوتيک ها مکانيسم عمل آنتی بيوتيک ها انواع آنتی بيوتيک ها مقاومت به آنتی بيوتيک ها

3. اهداف اختصاصي • پس از پايان اين جلسه انتظار مي رود كه فراگير: • پنج مکانيسم عمل آنتی بيوتيک ها را تشخيص دهد • توضيح دهد چرا آنتی بيوتيک ها به صورت اختصاصی بر روی باکتری ها اثر می کنند • مزايای پنی سيلين ها ی نيمه صناعی، سفالوسپورين ها و ونکومايسن را بيان نمايد • نحوه ممانعت از سنتز پروتئين توسط جنتامايسين، تتراسايکلين ،کلرامفنيکل و اريترومايسين را توضيح دهد • مکانيسم اثر پلی مکسين B و باسی تراسين را با هم مقايسه نمايد • توضيح دهد چگونه ريفامپين و سيپروفلوکساسين باعث مرگ باکتری ها می شوند • نحوه اثر سولوفوناميد ها بر روی باکتری ها توضيح دهد • مکانسم ها ی ايجاد مقاومت به آنتی بيوتک های مختلف را با ذکر مثال توضيح دهد • نحوه تعيين حساسيت باکتری به آنتی بيوتيک های مختلف در آزمايشگاه جهت انتخاب آنتی بيوتيک مناسب • برای درمان بيماری را توضيح دهد

4. The era of chemotherapy • 1910 • Paul Ehrlich • The German chemist • Discovered Salvarsan • Effective against Treponema pallidum

5. In 1928, Alexander Fleming's discovery of penicillin • In 1935, Gerhard Domagk's discovery of Sulfonamidochrysoidine • In 1943, Selman Waksman's discovery of streptomycin The era of chemotherapy

6. The Spectrum of Antimicrobial Activity • Narrow spectrum (limited spectrum) • Antimicrobials effective against a (limited spectrum) of microbial types • A drug effective on G+ or G- bacteria • Broad spectrum (extended spectrum) • Antimicrobials effective against a (extended spectrum) wide variety of microbial types • A drug effective against both G+& G- bacteria

7. The Action of Antimicrobial Drugs Bactericidal Kill microbes directly Bacteriostatic Prevent microbes from growing

8. Mechanisms of Antibiotics Action

9. Mechanisms of Antibiotics Action 1- Inhibition of Cell Wall Synthesis 2- Injuring the Plasma Membrane 3- Inhibition of Protein Synthesis 4- Inhibition of Nucleic Acid Synthesis 5- Inhibiting the Synthesis of Essential Metabolites

10. Penicillin-binding proteins (PBPs( Transpeptidases, Carboxypeptidases, Transglycosylases Inhibition of Cell Wall Synthesis β-Lactam antibiotics: generally are bactericidal agents

11. Inhibition of Cell Wall Synthesis • 1- Beta-Lactam Antibiotics • Penicillins • Cephalosporins • 2- Glycopeptides • Vancomycin • 3- Lipopeptides • Daptomycin • 4- Polypeptides • Bacitracin

12. R Thiazolidine β-lactam Beta-Lactam Antibiotics • Penicillins • 6-aminopenicillanic acid • Penicillium chrysogenum

13. Penicillin G Penicillin V NaturalPenicillins Penicillin G • Is incompletely absorbed • Inactivated by gastric acid • An intravenous drug Penicillin V • Resistant to acid • Oral form Active against All β-hemolytic & most other streptococci • Meningococci & most G+ anaerobes

14. Nafcillin Methicillin Cloxacillin Oxacillin Dicloxacillin Penicillinase resistant penicillins Nafcillin, Oxacillin, Methicillin, Cloxacillin, Dicloxacillin Similar to natural penicillins Enhanced activity against staphylococci

15. Ticarcillin Ampicillin Amoxicillin Carbenicillin Broad-spectrum penicillins • 1- Aminopenicillins:Ampicillin, Amoxicillin • Ampicillin was limited primarily to Escherichia & Proteus species • 2- Carboxypenicillins: Carbenicillin, Ticarcillin • Are effective against a broader range of G- bacteria • Klebsiella, Enterobacter, & Pseudomonas species

16. Piperacillin Mezlocillin Azlocillin Broad-spectrum penicillins 3- Ureidopenicillins: Azlocillin, Piperacillin, Mezlocillin

17. Clavulanic acid Tazobactam Sulbactam Analogues • Clavulanic acid, Sulbactam, Tazobactam • β- lactamase inhibitors • Irreversibly inactivate susceptible bacterial β- lactamases • Are relatively inactive by themselves • When combined with some penicillins are effective (ampicillin, amoxicillin, ticarcillin, piperacillin) Amoxicillin/clavulanic acid (Co-amoxiclav) Ampicillin/sulbactam (Sultamicillin)

18. R3 R1 β-lactam ring Dihydrothiazine ring R2 Cephalosporins • 7-aminocephalosporanic acid • Originally isolated from the mold Cephalosporium • Cephamycins • Contain O in place of S • More stable to β-lactamase hydrolysis

19. Cefazolin Cephradine Cephalexin First-generation (narrow-spectrum) Cefazolin, Cephalexin, Cephalothin, Cephapirin, Cephradine Escherichia coli Klebsiella species Proteus mirabilis Oxacillin-susceptible gram-positive cocci

20. Cefaclor Cefamandole Cefoxitin Second-generation(expanded-spectrum) Cefamandole, Cefaclor, Cefuroxime, Cefotetan, Cefoxitin Haemophilus influenzae Enterobacter species Citrobacter species Serratia species Some anaerobes, such as Bacteroides fragilis

21. Ceftriaxone Cefixime Ceftazidime Third-generation(broad-spectrum) Cefixime, Cefoperazone, Cefotaxime, Ceftazidime,Ceftizoxime, Ceftriaxone Most Enterobacteriaceae Pseudomonas aeruginosa

22. Cefpirome Fourth-generation Cefepime, Cefpirome Activity = oxacillin against gram-positive bacteria Improved gram negative activity

23. Ceftobiprole Ceftaroline acetate Fifth-generation Ceftobiprole, Ceftaroline

24. Ertapenem Meropenem Imipenem Carbapenems • Imipenem, Meropenem, Ertapenem • Broad-spectrum antibiotics • Active against virtually all organisms • Resistance has been reported • All oxacillin-resistant staphylococci • Selected Enterobacteriaceae • Pseudomonas

25. Aztreonam Monobactams • Aztreonam • Narrow-spectrum antibiotics • Are active only against aerobic, G- bacteria • Anaerobic bacteria and G+ bacteria are resistant

26. Resistant to β-lactam antibiotics • 1) Prevention of the interaction of the antibiotic & the target PBP Only in G- particularly Pseudomonas species Changes in the porins Alter the size or charge of channels • 2) Modification of the binding of the antibiotic to the PBP • I- A mutation in the PBP gene • Penicillin resistance in Enterococcus faecium • II- Modification of an existing PBP through recombination • Penicillin resistance in Streptococcus pneumoniae III- Acquisition of a new PBP • Escherichia coli , MRSA • IV- An overproduction of PBP • 3) Hydrolysis of the antibiotic by β-lactamases

27. β-lactamases • Serine proteases as the PBPs • > 200 different β-lactamases Penicillinases: specific for penicillins • Cephalosporinases: specific for cephalosporins • Carbapenemases: specific for carbapenems • Four classes (A to D)

28. β-lactamases • Class A • The most common are SHV-l & TEM-l • Found in G- rods (e.g., Escherichia, Klebsiella) • Minimal activity against cephalosporins • Point mutations: Extended-spectrum β-lactamases [ESBLs] Are commonly encoded on plasmids

29. β-lactamases • Class B • Zinc dependent metalloenzymes • Broad spectrum of activity against all β-lactam antibiotics • Class C • Are primarily cephalosporinases • Are encoded on the bacterial chromosome • Class D • Are penicillinases • Found primarily in G- rods

30. Vancomycin Glycopeptides: Vancomycin • Obtained from Streptomyces orientalis • Interacts with the D-alanine-D-alanine in the pentapeptide • Is inactive against G- bacteria • Intrinsically resistant • D-alanine-D-lactate • Lactobacillus, Erysipelothrix • D-alanine-D-serine • Enterococcus gallinarum, E. casseliflavus • Acquired resistance:vanA& vanB

31. Bacitracin Polypeptides: Bacitracin • Bacillus licheniformis • Interfering with dephosphorylation of the lipid carrier • Damage cytoplasmic membrane and inhibit RNA transcription • The treatment of skin infections caused by • Staphylococcus & group A Streptococcus • Used in creams, ointments, sprays • G- bacteria are resistant • Resistance: failure of the antibiotic to penetrate into the cell

32. Inhibition of Cell Wall Synthesis Isoniazid, Ethionamide, Ethambutol, & Cycloserine Used for the treatment of mycobacterial infections Isoniazid Isonicotinic acid hydrazide [INH]) Bactericidal; Blocks mycolic acid synthesis Ethionamide Derivative of INH Blocks mycolic acid synthesis Ethambutol Interferes with the synthesis of arabinogalactan in the cell wall Cycloserine Inhibits D-alanine-Dalanine synthetase & Alanine racemase

33. Injuring the Plasma Membrane 1- Lipopeptides Daptomycin 2- Polypeptides Polymyxins

34. Daptomycin Lipopeptides: Daptomycin • A naturally cyclic lipopeptide • Streptomyces roseosporus • Binds irreversibly to the CM. • Disruption of the ionic gradients • Active against G+ bacteria • G- bacteria are resistant

35. Colistin Polymyxin B Polypeptides: Polymyxins • Cyclic polypeptides • Bacillus polymyxa • Interacting with LPS & the phospholipids in the OM • Increased cell permeability • Polymyxin B & E (Colistin) causing seriousnephrotoxicity • Localized infections: external otitis, eye&skin infections

36. Inhibition of Protein Synthesis

37. Inhibition of Protein Synthesis

38. Streptomycin Aminoglycosides • Amino sugars --- Glycosidic Bond--- Aminocyclitol ring • Bactericidal • Bind irreversibly to ribosomal proteins Misreading of the messenger RNA (mRNA) • Premature release of the ribosome from mRNA • Streptomycin, Neomycin, Kanamycin, & Tobramycin Streptomyces species • Gentamicin & Sisomicin Micromonospora species • Amikacinfrom kanamycin • Netilmicin from sisomicin • Systemic infections caused by many G- rods

39. Aminoglycosides • Resistance • 1- Mutation of the ribosomal binding site • 2- Decreased uptake of the antibiotic (Anaerobic bacteria) • 3- Increased expulsion of the antibiotic from the cell • 4- Enzymatic modification • The most common mechanism of resistance • Phosphotransferases (APHs; 7 described) • Adenyltransferases (ANTs; 4 described) • Acetyltransferases (AACs; 4 described)

40. The staining of teeth associated with tetracycline use Tetracyclines • Broad-spectrum • Bacteriostatic • Tetracycline, Doxycycline, Minocycline • Binding reversibly to the 30S • Blocking the binding of aminoacyl-tRNA • Chlamydia, Mycoplasma, Rickettsia

41. Tetracyclines Resistance 1- Decreased penetration of the antibiotic 2- Active efflux of the antibiotic out of the cell 3- Alteration of the ribosomal target site 4- Enzymatic modification of the antibiotic

42. Glycylcycline • Tigecycline • Semisynthetic derivative of minocycline • Inhibits protein synthesis as the tetracyclines • Broad spectrum of activity: G+, G- & anaerobic bacteria • Resistant Bacteria Proteus • Morganella • Providencia • Pseudomonas aeruginosa

43. Oxazolidinones • Linezolid • Narrow-spectrum • Block initiation of protein synthesis (70S initiation complex) • Binds to the 50S ribosomal subunit • Mechanism of resistance Target site modification

44. C: Chloramphenicol M: Macrolides T: Tertracyclines

45. Chloramphenicol • Broad spectrum • Bacteriostatic • Blocking peptide elongation • Binding reversibly to the peptidyl transferase (50S) • Only for the treatment of typhoid fever • Can produce aplastic anemia(1 per 24,000 treated patients) • Resistance: plasmid-encoded chloramphenicol acetyltransferase

46. Desosamine Cladinose Macrolides Erythromycin, Azithromycin, Clarithromycin • Streptomyces erythreus • Broad spectrum • Bacteriostatic • Blocks polypeptide elongation Reversible binding to the 23S rRNA • Used to treat pulmonary infections Mycoplasma, Legionella, & Chlamydia species • Infections caused by Campylobacter species

47. Macrolides Resistance 1- Alteration of the ribosomal target site Methylation of the 23S rRNA 2- Enzymatic modification of the antibiotic Destruction of the lactone ring by an erythromycin esterase 3- Mutations in the 23S rRNA & ribosomal proteins

48. Ketolides • Telithromycin • Semisynthetic derivatives of erythromycin • Increase stability in acid • Blocks protein synthesis as Macrolides • Broad-spectrum antibiotic • Active against some macrolide resistant staphylococci & enterococci

49. E E E CD CD CD مقاومت پيوسته حساس مقاومت القايي Lincosamide • Clindamycin • Derivative of lincomycin (Streptomyces lincolnensi) • Inhibits peptidyl transferase • Block the binding of the amino acid-acyltRNA complex • Resistance: Methylation of the 23S ribosomal RNA

50. Streptogramin • Streptogramin • Cyclic peptides • Streptomyces species • Group A and group B • Quinupristin-dalfopristin (Synercid) • Dalfopristin prevents peptide chain elongation • Quinupristin initiates premature release of peptide