It contains complete details about beta lactam antibiotics

1. Beta Lactam Antibiotics
Presentation by:
Saurav Chandra Sarma
Int. Ph.D NCU 3rd Sem.

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. Antibiotics and it’s Classification

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. Classification of Antibiotics
Based on mode
of Action
Bacteriostatic Bactericidal
Based on their
spectrum of
action
Broad-spectrum
Narrow
Spectrum

6. Source: Google Images

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. Types of Antibiotics
(Based on their structural similarities)

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. Antibiotic Targets
Sourcs: Microbiology: A Clinical Approach

11. Bacterial Cell structure

12. Gram positive vs. Gram negative
bacteria
Source: Google Images

13. Cell Wall
Source: Google Images

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. 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. Transpeptidation mechanism
Source: Google Images

17. Transpeptidation mechanism
Source: Google Images

18. Beta–lactam Drugs

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. Classification
•Penicillins
•Cephalosporins
•Other β-Lactam drugs
--Cephamycins
--Carbapenems
--Oxacephalosporins
--β-Lactamase inhibitors
--Monolactams

21. Beta-Lactam Structure

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. 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. 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. 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

27. 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.

28. Mechanism of β-Lactam Drugs
The hydroxyl attacks the amide and forms a
tetrahedral intermediate.

29. Mechanism of β-Lactam Drugs
The tetrahedral intermediate collapses, the amide
bond is broken, and the nitrogen is reduced.

30. Mechanism of β-Lactam Drugs
The PBP is now covalently bound by the drug and
cannot perform the cross linking action.

31. Penicillin

32. Natural Penicillin

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. 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

35. Amino-Penicillin
Ampicillin R=Ph
Amoxicillin R= Ph-OH

36. 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

37. 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

38. Anti-Staphylococcal Penicillin

39. Methicillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT FOR:
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Interstitial nephritis

40. 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

41. 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

42. Cloxacillin
EFFECTIVE AGAINST:
• Staphylococci that produce
beta-lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction

43. 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

44. 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

45. Anti-Pseudomonal Penicillin

46. 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

47. 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

48. Ticarcillin
EFFECTIVE AGAINST:
• Mainly gram negative bacteria
particularly Pseudomonas aeruginosa
TREATMENT FOR:
• Stenotrophomonas maltophilia
infections
CHARACTERISTICS:
SIDE-EFFECT:
• Diarrhoea
• Bleeding
• Fever
• Fainting

49. Cephalosporin

51. 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).

52. First Generation Cephalosporins
Cefalothin Cefalexin
Cefadroxil Cefazolin

53. Second Generation Cephalosporins
Cefuroxime(Oral) Cefotetan

54. Third Generation Cephalosporins
Cefotaxime Ceftriaxone
Ceftazidime

55. Fourth Generation Cephalosporins
Cefepime

56. Carbapenem

57. 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

58. 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

59. 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

60. 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

61. 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

62. Monobactam

63. 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

64. 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

65. Beta–lactam Resistance

66. 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

67. 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.

68. Porins
Altered penicillin binding proteins
b-lactamases
MECHANISMS OF RESISTANCE

69. MECHANISMS FOR ACQUIRING
RESISTANCE
69

70. 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

71. Beta–lactamases

72. Beta-Lactamase Enzyme
Functional
Classification
Group 1
(Cephalosporinases*)
Group 2
(Penicillinases,
Cephalosporinases)
Group 3
(Metalloenzymes*)
Group 4
(Penicillinases*)
* Not inhibited by Clavulanic Acid

73. Beta-Lactamase Enzyme
Molecular
Classification
Serine Based
Class A Class C Class D
Metallo
B-lactamases
Class B

74. Beta-Lactamase Enzyme
Molecular
Classification
Serine Based
Class A Class C Class D
Metallo
B-lactamases
Class B

75. 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)

76. 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

77. 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

78. 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.

79. 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