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Beta Lactam Antibiotics

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Beta Lactam Antibiotics

  1. 1. Beta Lactam Antibiotics Presentation by: Saurav Chandra Sarma Int. Ph.D NCU 3rd Sem.
  2. 2. Outline 1 • What is Antibiotic??? • Bacterial cell structure 2 • Beta-lactam Antibiotics and it’s mode of action • Resistance to Beta lactam Antibiotics • Examples 3 • Beta-lactamases and its classification • Proposal • Conclusion.!!!
  3. 3. Antibiotics and it’s Classification
  4. 4. Antibiotics •An antibiotic is an agent that either kills or inhibits the growth of a microorganism. •Excludes substances that kill bacteria but that are not produced by microorganisms such as Gastric juices & Hydrogen Peroxide. •Also excludes synthetic antibacterial compound such as sulfonamides. •Penicillin is the first natural antibiotic discovered by Alexander Fleming in 1928.
  5. 5. Classification of Antibiotics Based on mode of Action Bacteriostatic Bactericidal Based on their spectrum of action Broad-spectrum Narrow Spectrum
  6. 6. Source: Google Images
  7. 7. Types of Antibiotics (Based on their mode of action) Bacteriostatic Antibiotics • Tetracyclines • Spectinomycin • Sulphonamides • Macrolides • Chloramphenicol • Trimethoprim Bactericidal Antibiotics • Penicillins • Cephalosporins • Fluoroquinolones (Ciprofloxacin) • Glycopeptides (Vancomycin) • Monobactams • Carbapenems
  8. 8. Types of Antibiotics (Based on their structural similarities)
  9. 9. Antibiotics: Mode of Action •Inhibitors of DNA synthesis •Inhibitors of bacterial protein synthesis •Inhibitors of bacterial cell wall synthesis •Interference with metabolism •Impairment of nucleic acids
  10. 10. Antibiotic Targets Sourcs: Microbiology: A Clinical Approach
  11. 11. Bacterial Cell structure
  12. 12. Gram positive vs. Gram negative bacteria Source: Google Images
  13. 13. Cell Wall Source: Google Images
  14. 14. Structure of Peptidoglycan layer •Peptidoglycan is a carbohydrate composed of alternating units of NAMA and NAGA. •The NAMA units have a peptide side chain which can be cross linked from the L-Lys residue to the terminal D-Ala-D- Ala link on a neighboring NAMA unit. Source: Google Images
  15. 15. Transpeptidase Enzyme •The cross linking reaction is catalyzed by a class of transpeptidases known as penicillin binding proteins •A critical part of the process is the recognition of the D-Ala-D-Ala sequence of the NAMA peptide side chain by the PBP. Interfering with this recognition disrupts the cell wall synthesis. •β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross- linking process. Source: Google Images
  16. 16. Transpeptidation mechanism Source: Google Images
  17. 17. Transpeptidation mechanism Source: Google Images
  18. 18. Beta–lactam Drugs
  19. 19. Beta-Lactam Antibiotics β-lactam ring •Contains a beta-lactam ring in their molecular structures. •Nitrogen is attached to the beta carbon relative to the carbonyl ring and hence the name.
  20. 20. Classification •Penicillins •Cephalosporins •Other β-Lactam drugs --Cephamycins --Carbapenems --Oxacephalosporins --β-Lactamase inhibitors --Monolactams
  21. 21. Beta-Lactam Structure
  22. 22. How do they work? 1. The β-lactam binds to Penicillin Binding Protein (PBP) 2. PBP is unable to crosslink peptidoglycan chains 3. The bacteria is unable to synthesize a stable cell wall 4. The bacteria is lysed
  23. 23. Mechanism of β-Lactam Drugs • The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl. • β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner. • This reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy.
  24. 24. Discovery of Penicillin(First beta- lactam drug) •Discovered in 1928. • While working in his lab, trying to kill a deadly bacteria,he noticed a blue mold growing on the dish •Learned that it was the mold Penicillum Notatum. •Penicillin is found in this mold. •Noticed that the bacteria around the mold was dissolving. Source: Google Images
  25. 25. How it is was Developed • For 9 years, nobody could purify the Penicillum Notatum to get the pure penicillin. Finally, in 1938, a team of Oxford University Scientists, headed by Howard Florey and Ernst B. Chain helped to develop penicillin. Source: Google Images
  26. 26. Mechanism of β-Lactam Drugs • The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl. • β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner. • This reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy.
  27. 27. Mechanism of β-Lactam Drugs The hydroxyl attacks the amide and forms a tetrahedral intermediate.
  28. 28. Mechanism of β-Lactam Drugs The tetrahedral intermediate collapses, the amide bond is broken, and the nitrogen is reduced.
  29. 29. Mechanism of β-Lactam Drugs The PBP is now covalently bound by the drug and cannot perform the cross linking action.
  30. 30. Penicillin
  31. 31. Natural Penicillin
  32. 32. Penicillin V (Phenoxymethylpenicillin) EFFECTIVE AGAINST: • Gram positive + Less effective against Gram negative bacteria TREATMENT FOR: • Tonsillitis • Anthrax • Rheumatic fever • Streptococcal skin infections CHARACTERISTICS: • Narrow spectrum • Should be given orally • Prone to beta-lactamase
  33. 33. Penicillin V (Phenoxymethylpenicillin) EFFECTIVE AGAINST: • Gram positive + Less effective against Gram negative bacteria TREATMENT FOR: • Tonsillitis • Anthrax • Rheumatic fever • Streptococcal skin infections CHARACTERISTICS: • Narrow spectrum • Should be given orally • Prone to beta-lactamase
  34. 34. Amino-Penicillin Ampicillin R=Ph Amoxicillin R= Ph-OH
  35. 35. Ampicillin EFFECTIVE AGAINST: • Gram positive + Gram negative bacteria TREATMENT FOR: • Ear infection • Sinusitis • Urinary tract infections • Meningitis CHARACTERISTICS: • Broad spectrum • Can be given orally and parenterally • Prone to beta-lactamase Ampicillin Sulbactam + ll Unasyn
  36. 36. Amoxicillin EFFECTIVE AGAINST: • Gram positive + Gram negative bacteria TREATMENT FOR: • Skin infection • Sinusitis • Urinary tract infections • Streptococcal pharyngitis CHARACTERISTICS: • Broad spectrum • Can be given orally and parenterally • Prone to beta-lactamase SIDE-EFFECTS: • Rash, diarrhea, vomiting, nausea, edema, stomatitis, and easy fatigue. Amoxicillin Clavulanic Acid + ll Augmentin
  37. 37. Anti-Staphylococcal Penicillin
  38. 38. Methicillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT FOR: CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Interstitial nephritis
  39. 39. Oxacillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT AGAINST: • penicillin-resistant Staphylococcus aureus CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Hypersensitivity and local reactions • In high doses, renal, hepatic, or nervous system effects can occur
  40. 40. Nafcillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT AGAINST: • Staphylococcal infections CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Allergic reactions • Nausea and vomiting • Abdominal pain
  41. 41. Cloxacillin EFFECTIVE AGAINST: • Staphylococci that produce beta-lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction
  42. 42. Dicloxacillin EFFECTIVE AGAINST: • Gram positive bacteria + Staphylococci that produce beta- lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction • Diarrhoea, nausea, rash, urticaria pain and inflammation at injection site
  43. 43. Flucloxacillin EFFECTIVE AGAINST: • Gram positive bacteria + Staphylococci that produce beta- lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction • Diarrhoea, nausea, rash, urticaria pain and inflammation at injection site
  44. 44. Anti-Pseudomonal Penicillin
  45. 45. Piperacillin EFFECTIVE AGAINST: • Gram positive +Gram negative CHARACTERISTICS: • Extended Spectrum • Should be given by intravenous or intramuscular injection SIDE-EFFECT: • Hypersensitivity • Gastrointestinal • Renal • Nervous system *Piperacillin+Tazobactam=Zosyn
  46. 46. Carbenicillin EFFECTIVE AGAINST: • Gram negative + Limited Gram positive TREATMENT FOR: • Urinary tract infections CHARACTERISTICS: • Highly soluble in water and acid- labile SIDE-EFFECT: • High doses can cause bleeding • Hypokalemia
  47. 47. Ticarcillin EFFECTIVE AGAINST: • Mainly gram negative bacteria particularly Pseudomonas aeruginosa TREATMENT FOR: • Stenotrophomonas maltophilia infections CHARACTERISTICS: SIDE-EFFECT: • Diarrhoea • Bleeding • Fever • Fainting
  48. 48. Cephalosporin
  49. 49. These has been conventionally classified into four generations based on Generation system • This is based on chronological sequence of development, but more importantly ,takes into consideration the overall antibacterial spectrum as well as potency. • First-generation cephalosporins are predominantly active against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).
  50. 50. First Generation Cephalosporins Cefalothin Cefalexin Cefadroxil Cefazolin
  51. 51. Second Generation Cephalosporins Cefuroxime(Oral) Cefotetan
  52. 52. Third Generation Cephalosporins Cefotaxime Ceftriaxone Ceftazidime
  53. 53. Fourth Generation Cephalosporins Cefepime
  54. 54. Carbapenem
  55. 55. What are carbapenems • Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to beta- lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya. 57Dr.T.V.Rao MD
  56. 56. Carbapenems common uses • Imipenem – Broad spectrum, covers Gram-positive, Gram-negative (including ESBL-producing strains), Pseudomonas and anaerobes • Meropenem – Less seizure-inducing potential, can be used to treat CNS infections • Ertapenem – Lacks activity vs. Acinetobacter and Pseudomonas – Has limited activity against penicillin-resistant pneumococci 58Dr.T.V.Rao MD
  57. 57. Imipenem EFFECTIVE AGAINST: • Aerobic and anaerobic, Gram positive and gram negative bacteria CHARACTERISTICS: • Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes SIDE-EFFECT: • Seizuregenic at high doses
  58. 58. Meropenem EFFECTIVE AGAINST: • Aerobic and anaerobic, Gram positive and gram negative bacteria CHARACTERISTICS: • Ultra Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes SIDE-EFFECT: • Diarrhoea • Vomiting • headache
  59. 59. Ertapenem EFFECTIVE AGAINST: • Gram positive and gram negative bacteria CHARACTERISTICS: • Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes • Not active against MRSA SIDE-EFFECT: • Convulsions • Seizures • headache
  60. 60. Monobactam
  61. 61. Aztreonam EFFECTIVE AGAINST: • Gram positive +Gram negative+Anaerobic bacteria CHARACTERISTICS: • Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes • Not active against MRSA SIDE-EFFECT: • Diarrhoea • Nausea • Vomiting
  62. 62. BETA-LACTAMASE INHIBITORS • Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction • Most successful when they bind the β-lactamase irreversibly • Three important in medicine: » Clavulanic Acid » Sulbactam » Tazobactam
  63. 63. Beta–lactam Resistance
  64. 64. Resistance-The Global Battle.!!! What is Resistance? •Drug resistance refers to unresponsiveness of a microorganism to an antimicrobial agent. •Drug resistance are of two types: ---Natural Resistance ---Acquired Resistance
  65. 65. Natural Resistance: •Some microbes have always been resistant to certain anti-microbial agent. •They lack the metabolic process or the target side thai is affected by particular drug. E.g: Gram negative bacilli are normally unaffected by Penicillin G. M. tuberculosis is insensitive to Tetracyclines. •This type of resistance does not pose significant clinical problem. Acquired Resistance: •It is the development of resistance by an organism which was sensiive before due to the use of antimicrobial agent over a period of time. •This can happen with any microbe and is a major clinical problem. However, the development of resistance is dependent on the microorganism as well as the drug.
  66. 66. Porins Altered penicillin binding proteins b-lactamases MECHANISMS OF RESISTANCE
  67. 67. MECHANISMS FOR ACQUIRING RESISTANCE 69
  68. 68. CHALLENGES OF b-LACTAMASES 1940 : Introduction of penicillins 1940 : First description of b-lactamases published 1944 : Strains of staphylococcus aureus producing b-lactamase 1960s : Clinical use of expanded spectrum penicillins - such as ampicillin and carbenicillin 1970s : plasmid mediated b-lactamases assumed prominence in enterobacteriaceae and gram-negative bacteria 1980-90 : Development of broad-spectrum cephalosporins, cephamycins, monobactams and carbapenems 1990 : Increased resistance among gram-negative bacteria with inducible chromosomally-mediated b lactamases JAC (1993); suppl A: 1-8
  69. 69. Beta–lactamases
  70. 70. Beta-Lactamase Enzyme Functional Classification Group 1 (Cephalosporinases*) Group 2 (Penicillinases, Cephalosporinases) Group 3 (Metalloenzymes*) Group 4 (Penicillinases*) * Not inhibited by Clavulanic Acid
  71. 71. Beta-Lactamase Enzyme Molecular Classification Serine Based Class A Class C Class D Metallo B-lactamases Class B
  72. 72. Beta-Lactamase Enzyme Molecular Classification Serine Based Class A Class C Class D Metallo B-lactamases Class B
  73. 73. ESBLs are enzymes that mediate resistance to extended-spectrum (third generation) cephalosporins (e.g., ceftazidime, cefotaxime, and ceftriaxone) and monobactams (e.g., aztreonam) but do not affect cephamycins (e.g., cefoxitin and Cefotetan) or carbapenems (e.g., meropenem or imipenem). Extended spectra Beta-Lactamase (ESBL)
  74. 74. WHY SHOULD WE DETECT THESE ENZYMES? • The presence of an ESBL-producing organism in a clinical infection can result in treatment failure if one of the above classes of drugs is used. • ESBLs can be difficult to detect because they have different levels of activity against various cephalosporins. Thus, the choice of which antimicrobial agents to test is critical. For example, one enzyme may actively hydrolyze ceftazidime, resulting in ceftazidime minimum inhibitory concentrations (MICs) of 256 µg/ml, but have poor activity on cefotaxime, producing MICs of only 4 µg/ml. • If an ESBL is detected, all penicillin's, cephalosporins, and aztreonam should be reported as resistant, even if in vitro test results indicate susceptibility
  75. 75. RISK FACTORS FOR ESBL INFECTION • Length of hospital stay • Severity of illness • Time in the ICU • Intubation and mechanical ventilation • Urinary or arterial catheterization • Previous exposure to antibiotics
  76. 76. Metallo Beta-lactamase • Resistant against broad spectrum of beta-lactam antibiotics • These include the antibiotics of the carbapenem family. • This class of β-lactamases is characterized by the ability to hydrolyze carbapenems and by its resistance to the commercially available β-lactamase inhibitors but susceptibility to inhibition by metal ion chelators. • The most common bacteria that make this enzyme are Gram negative such as Escherichia coli and Klebsiella pneumoniae , Pseudomonas aeroginosa.
  77. 77. BETA-LACTAMASE INHIBITORS • Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction • Most successful when they bind the β-lactamase irreversibly • Three important in medicine: » Clavulanic Acid » Sulbactam » Tazobactam

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