Antibiotics

1
Antibiotics
2
Step 1 How to Kill a Bacterium.

• What are the bacterial weak points?
• Specifically, which commercial antibiotics target
  each of these points?

3
Target 1 The Bacterial Cell Envelope
4
Structure of the bacterial cell envelope.
Gram-positive. Gram-negative.
5
Structure of peptidoglycan. Peptidoglycan
synthesis requires cross-linking of disaccharide
polymers by penicillin-binding proteins (PBPs).
NAMA, N-acetyl-muramic acid NAGA,
N-acetyl-glucosamine.
6
Antibiotics that Target the Bacterial Cell
Envelope Include

• The b-Lactam Antibiotics
• Vancomycin
• Daptomycin

7
Target 2 The Bacterial Process of Protein
Production
8
An overview of the process by which proteins are
produced within bacteria.
9
Structure of the bacterial ribosome.
10
Antibiotics that Block Bacterial Protein
Production Include

• Rifamycins
• Aminoglycosides
• Macrolides and Ketolides
• Tetracyclines and Glycylcyclines
• Chloramphenicol
• Clindamycin
• Streptogramins
• Linezolid (member of Oxazolidinone Class)

11
Target 3 DNA and Bacterial Replication
12
Bacterial synthesis of tetrahydrofolate.
13
Supercoiling of the double helical structure of
DNA. Twisting of DNA results in formation of
supercoils. During transcription, the movement
of RNA polymerase along the chromosome results in
the accumulation of positive supercoils ahead of
the enzyme and negative supercoils behind it.
(Adapted with permission from Alberts B, Johnson
A, Lewis J, et al. Molecular Biology of the Cell.
New York Garland Science, 2002314.)
14
Replication of the bacterial chromosome. A
consequence of the circular nature of the
bacterial chromosome is that replicated
chromosomes are interlinked, requiring
topoisomerase for appropriate segregation.
15
Antibiotics that Target DNA and Replication
Include

• Sulfa Drugs
• Quinolones
• Metronidazole

16
Which Bacteria are Clinically Important?
17
General Classes of Clinically Important Bacteria
Include

• Gram-positive aerobic bacteria
• Gram-negative aerobic bacteria
• Anaerobic bacteria (both Gram and -)
• Atypical bacteria
• Spirochetes
• Mycobacteria

18
Gram-positive Bacteria of Clinical Importance

• Staphylococci
• Staphylococcus aureus
• Staphylococcus epidermidis
• Streptococci
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Streptococcus agalactiae
• Streptococcus viridans
• Enterococci
• Enterococcus faecalis
• Enterococcus faecium
• Listeria monocytogenes
• Bacillus anthracis

19
Gram-negative Bacteria of Clinical Importance

• Enterobacteriaceae
• Escherichia coli, Enterobacter, Klebsiella,
  Proteus, Salmonella, Shigella, Yersinia, etc.
• Pseudomonas aeruginosa
• Neisseria
• Neisseria meningitidis and Neisseria gonorrhoeae
• Curved Gram-negative Bacilli
• Campylobacter jejuni, Helicobacter pylori, and
  Vibrio cholerae
• Haemophilus Influenzae
• Bordetella Pertussis
• Moraxella Catarrhalis
• Acinetobacter baumannii

20
Anaerobic Bacteria of Clinical Importance

• Gram-positive anaerobic bacilli
• Clostridium difficile
• Clostridium tetani
• Clostridium botulinum
• Gram-negative anaerobic bacilli
• Bacteroides fragilis

21
Atypical Bacteria of Clinical Importance Include

• Chlamydia
• Mycoplasma
• Legionella
• Brucella
• Francisella tularensis
• Rickettsia

22
Spirochetes of Clinical Importance Include

• Treponema pallidum
• Borrelia burgdorferi
• Leptospira interrogans

23
Mycobacteria of Clinical Importance Include

• Mycobacterium tuberculosis
• Mycobacterium avium
• Mycobacterium leprae

24
(No Transcript)
25
Antibiotics that Target the Bacterial Cell
Envelope

• The b-Lactam Antibiotics

26
Mechanism of action of ß-lactam antibiotics.
Normally, a new subunit of N-acetylmuramic acid
(NAMA) and N-acetylglucosamine (NAGA)
disaccharide with an attached peptide side chain
is linked to an existing peptidoglycan polymer.
This may occur by covalent attachment of a
glycine () bridge from one peptide side chain to
another through the enzymatic action of a
penicillin-binding protein (PBP). In the
presence of a ß-lactam antibiotic, this process
is disrupted. The ß-lactam antibiotic binds the
PBP and prevents it from cross-linking the
glycine bridge to the peptide side chain, thus
blocking incorporation of the disaccharide
subunit into the existing peptidoglycan polymer.
27
Mechanism of penicillin-binding protein (PBP)
inhibition by ß-lactam antibiotics. PBPs
recognize and catalyze the peptide bond between
two alanine subunits of the peptidoglycan peptide
side chain. The ß-lactam ring mimics this
peptide bond. Thus, the PBPs attempt to catalyze
the ß-lactam ring, resulting in inactivation of
the PBPs.
28

• Six P's by which the action of ß-lactams may be
  blocked
• penetration,
• porins,
• pumps,
• penicillinases (ß-lactamases),
• penicillin-binding proteins (PBPs), and
• peptidoglycan.

29
(No Transcript)
30
The Penicillins
Category Parenteral Agents Oral Agents
Natural Penicillins Penicillin G Penicillin V
Antistaphylococcal penicillins Nafcillin, oxacillin Dicloxacillin
Aminopenicillins Ampicillin Amoxicillin and Ampicillin
Aminopenicillin b-lactamase inhibitor Ampicillin-sulbactam Amoxicillin-clavulanate
Extended-spectrum penicillin Piperacillin, ticaricillin Carbenicillin
Extended-spectrum penicillin b-lactamase inhibitor Piperacillin-tazobactam, ticaricillin-clavulanate
31
INTRODUCTION

• Antibacterial agents which inhibit bacterial cell
  wall synthesis
• Discovered by Fleming from a fungal colony (1928)
  
• Shown to be non toxic and antibacterial
• Isolated and purified by Florey and Chain (1938)
• First successful clinical trial (1941)
• Produced by large scale fermentation (1944)
• Structure established by X-Ray crystallography
  (1945)
• Full synthesis developed by Sheehan (1957)
• Isolation of 6-APA by Beechams (1958-60) -
  development of semi-synthetic penicillins
• Discovery of clavulanic acid and b-lactamase
  inhibitors

32
http//www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/Spencer/spencer_cellwall.h
tml
33
STRUCTURE
Side chain varies depending on carboxylic acid
present in fermentation medium
34
Shape of Penicillin G
Folded envelope shape
35
Properties of Penicillin G

• Active vs. Gram ve bacilli and some Gram -ve
  cocci
• Non toxic
• Limited range of activity
• Not orally active - must be injected
• Sensitive to b-lactamases (enzymes which
  hydrolyse the b-lactam ring)
• Some patients are allergic
• Inactive vs. Staphylococci

Drug Development

• Aims
• To increase chemical stability for oral
  administration
• To increase resistance to b-lactamases
• To increase the range of activity

36
SAR

• Conclusions
• Amide and carboxylic acid are involved in binding
• Carboxylic acid binds as the carboxylate ion
• Mechanism of action involves the b-lactam ring
• Activity related to b-lactam ring strain
• (subject to stability factors)
• Bicyclic system increases b-lactam ring strain
• Not much variation in structure is possible
• Variations are limited to the side chain (R)

37
Mechanism of action

• Penicillins inhibit a bacterial enzyme called the
  transpeptidase enzyme which is involved in the
  synthesis of the bacterial cell wall
• The b-lactam ring is involved in the mechanism of
  inhibition
• Penicillin becomes covalently linked to the
  enzymes active site leading to irreversible
  inhibition

Covalent bond formed to transpeptidase
enzyme Irreversible inhibition
38
Mechanism of action - bacterial cell wall
synthesis
39
Mechanism of action - bacterial cell wall
synthesis
40
Mechanism of action - bacterial cell wall
synthesis

• Penicillin inhibits final crosslinking stage of
  cell wall synthesis
• It reacts with the transpeptidase enzyme to form
  an irreversible covalent bond
• Inhibition of transpeptidase leads to a weakened
  cell wall
• Cells swell due to water entering the cell, then
  burst (lysis)
• Penicillin possibly acts as an analogue of the
  L-Ala-g-D-Glu portion of the pentapeptide chain.
  However, the carboxylate group that is essential
  to penicillin activity is not present in this
  portion

41
Mechanism of action - bacterial cell wall
synthesis
Alternative theory- Pencillin mimics D-Ala-D-Ala.
42
Mechanism of action - bacterial cell wall
synthesis
Alternative theory- Penicillin mimics D-Ala-D-Ala.
43
Mechanism of action - bacterial cell wall
synthesis
Penicillin can be seen to mimic acyl-D-Ala-D-Ala
44
Penicillin Analogues - Preparation

• 1) By fermentation
• vary the carboxylic acid in the fermentation
  medium
• limited to unbranched acids at the a-position
  i.e. RCH2CO2H
• tedious and slow
• 2) By total synthesis
• only 1 overall yield (impractical)
• 3) By semi-synthetic procedures
• Use a naturally occurring structure as the
  starting material for analogue synthesis

45
Penicillin Analogues - Preparation
46
Penicillin Analogues - Preparation
Problem - How does one hydrolyse the side chain
by chemical means in presence of a labile
b-lactam ring?
Answer - Activate the side chain first to make it
more reactive
Note - Reaction with PCl5 requires involvement of
nitrogens lone pair of electrons. Not possible
for the b-lactam nitrogen.
47
Problems with Penicillin G

• It is sensitive to stomach acids
• It is sensitive to b-lactamases - enzymes which
  hydrolyse the b-lactam ring
• it has a limited range of activity

48
Problem 1 - Acid Sensitivity
Reasons for sensitivity
1) Ring Strain
49
Problem 1 - Acid Sensitivity
Reasons for sensitivity
2) Reactive b-lactam carbonyl group Does not
behave like a tertiary amide
X

• Interaction of nitrogens lone pair with the
  carbonyl group is not possible
• Results in a reactive carbonyl group

50
Problem 1 - Acid Sensitivity
Reasons for sensitivity
3) Acyl Side Chain - neighbouring group
participation in the hydrolysis mechanism
51
Problem 1 - Acid Sensitivity
Conclusions

• The b-lactam ring is essential for activity and
  must be retained
• Therefore, cannot tackle factors 1 and 2
• Can only tackle factor 3

Strategy Vary the acyl side group (R) to make it
electron withdrawing to decrease the
nucleophilicity of the carbonyl oxygen
52
Problem 1 - Acid Sensitivity
Examples

• Very successful semi-synthetic penicillins
• e.g. ampicillin, oxacillin

• Better acid stability and orally active
• But sensitive to b-lactamases
• Slightly less active than Penicillin G
• Allergy problems with some patients

53
Natural penicillins include Penicillin G
(parenteral) and Penicillin V (oral)
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Some Streptococcus pneumoniae, Some Enterococci, Listeria monocytogenes
Gram-negative bacterai Neisseria meningitidis, Some Haemophilus influenzae
Anaerobic bacteria Clostridia spp. (except C. difficile), Antinomyces israelii
Spirochetes Treponema pallidum Leptospira spp.
54
Problem 2 - Sensitivity to b-Lactamases
Notes on b-Lactamases

• Enzymes that inactivate penicillins by opening
  b-lactam rings
• Allow bacteria to be resistant to penicillin
• Transferable between bacterial strains (i.e.
  bacteria can acquire resistance)
• Important w.r.t. Staphylococcus aureus infections
  in hospitals
• 80 Staph. infections in hospitals were resistant
  to penicillin and other antibacterial agents by
  1960
• Mechanism of action for lactamases is identical
  to the mechanism of inhibition for the target
  enzyme
• But product is removed efficiently from the
  lactamase active site

55
Problem 2 - Sensitivity to b-Lactamases
Strategy

• Block access of penicillin to active site of
  enzyme by introducing bulky groups to the side
  chain to act as steric shields
• Size of shield is crucial to inhibit reaction of
  penicillins with b-lactamases but not with the
  target enzyme (transpeptidase)

56
Problem 2 - Sensitivity to b-Lactamases
Examples - Methicillin (Beechams - 1960)

• Methoxy groups block access to b-lactamases but
  not to transpeptidases
• Active against some penicillin G resistant
  strains (e.g. Staphylococcus)
• Acid sensitive (no e-withdrawing group) and must
  be injected
• Lower activity w.r.t. Pen G vs. Pen G sensitive
  bacteria (reduced access
• to transpeptidase)
• Poorer range of activity
• Poor activity vs. some streptococci
• Inactive vs. Gram -ve bacteria

57
Problem 2 - Sensitivity to b-Lactamases
Examples - Oxacillin
Oxacillin R R' H Cloxacillin R
Cl, R' H Flucloxacillin R Cl, R' F

• Orally active and acid resistant
• Resistant to b-lactamases
• Active vs. Staphylococcus aureus
• Less active than other penicillins
• Inactive vs. Gram -ve bacteria
• Nature of R R influences absorption and plasma
  protein binding
• Cloxacillin better absorbed than oxacillin
• Flucloxacillin less bound to plasma protein,
  leading to higher
• levels of free drug

58
Antistaphylococcal Penicillins include Nafcillin
and Oxacillin (parenteral) as well as
Dicloxacillin (oral)
Gram-positive bacteria Some Staphylococcus aureus, Some Staphylococcus epidermidis
59
Problem 3 - Range of Activity

• Factors
• Cell wall may have a coat preventing access to
  the cell
• Excess transpeptidase enzyme may be present
• Resistant transpeptidase enzyme (modified
  structure)
• Presence of b-lactamases
• Transfer of b-lactamases between strains
• Efflux mechanisms

• Strategy
• The number of factors involved make a single
  strategy
• impossible
• Use trial and error by varying R groups on the
  side chain
• Successful in producing broad spectrum
  antibiotics
• Results demonstrate general rules for broad
  spectrum activity.

60
Problem 3 - Range of Activity
Results of varying R in Pen G

• R hydrophobic results in high activity vs. Gram
  ve bacteria and poor activity vs. Gram -ve
  bacteria
• Increasing hydrophobicity has little effect on
  Gram ve activity but lowers Gram -ve activity
• Increasing hydrophilic character has little
  effect on Gram
• ve activity but increases Gram -ve activity
• Hydrophilic groups at the a-position (e.g. NH2,
  OH, CO2H) increase activity vs Gram -ve bacteria

61
Problem 3 - Range of Activity
Examples of Aminopenicillins include
Class 1 - NH2 at the a-position Ampicillin and
Amoxycillin (Beecham, 1964)
Ampicillin (Penbritin) 2nd most used penicillin
Amoxycillin (Amoxil)
62
Problem 3 - Range of Activity
Examples of Aminopenicillins Include

• Active vs Gram ve bacteria and Gram -ve bacteria
  which do not produce b-lactamases
• Acid resistant and orally active
• Non toxic
• Sensitive to b-lactamases
• Increased polarity due to extra amino group
• Poor absorption through the gut wall
• Disruption of gut flora leading to diarrhoea
• Inactive vs. Pseudomonas aeruginosa

Properties
63
Problem 3 - Range of Activity
Prodrugs of Ampicillin (Leo Pharmaceuticals -
1969)

• Properties
• Increased cell membrane permeability
• Polar carboxylic acid group is masked by the
  ester
• Ester is metabolised in the body by esterases to
  give the free drug

64
Problem 3 - Range of Activity
Mechanism

• Ester is less shielded by penicillin nucleus
• Hydrolysed product is chemically unstable and
  degrades
• Methyl ester of ampicillin is not hydrolysed in
  the
• body - bulky penicillin nucleus acts as a steric
  shield

65
The aminopenicillins include Ampicillin
(parenteral) as well as Amoxicillin and
Ampicillin (both oral)
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria Neisseria meningitidis, Some Haemophilus influenzae, Some Enterobacteriaceae
Anaerobic bacteria Clostridia spp. (except C. difficile), Antinomyces israelii
Spirochetes Borrelia burgdorferi
66
b-Lactamase Inhibitors
Clavulanic acid (Beechams 1976)(from Streptomyces
clavuligerus)

• Weak, unimportant antibacterial activity
• Powerful irreversible inhibitor of b-lactamases -
  suicide substrate
• Used as a sentry drug for ampicillin
• Augmentin ampicillin clavulanic acid
• Allows less ampicillin per dose and an increased
  activity spectrum
• Timentin ticarcillin clavulanic acid

67
b-Lactamase Inhibitors
Clavulanic acid - mechanism of action
68
b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives

• Suicide substrates for b-lactamase enzymes
• Sulbactam has a broader spectrum of activity vs
  b-lactamases than clavulanic acid, but is less
  potent
• Unasyn ampicillin sulbactam
• Tazobactam has a broader spectrum of activity vs
  b-lactamases than clavulanic acid, and has
  similar potency
• Tazocin or Zosyn piperacillin tazobactam

69
The aminopenicillins b-lactamase inhibitor
combinations include ampicillin-sulbactam
(parenteral) and amoxicillin-clavulanate (oral)
Gram-positive bacteria Some Staphylococcus aureus, Streptococcus pyogenes, Viridans streptococci, Some Streptoocus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria Neisseria spp. Haemophilus influenzae, Many Enterobacteriaceae
Anaerobic bacteria Clostridia spp. (except C. difficile), Actinomyces israellii, Bacteroides spp.
Spirochetes Borrelia burgdorferi
70
Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at the a-position
(carboxypenicillins)
Examples
R H CARBENICILLIN R Ph CARFECILLIN

• Carfecillin prodrug for carbenicillin
• Active over a wider range of Gram -ve bacteria
  than ampicillin
• Active vs. Pseudomonas aeruginosa
• Resistant to most b-lactamases
• Less active vs Gram ve bacteria (note the
  hydrophilic group)
• Acid sensitive and must be injected
• Stereochemistry at the a-position is important
• CO2H at the a-position is ionised at blood pH

71
Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at a-position (carboxypenicillins)
Examples

• Administered by injection
• Identical antibacterial spectrum to carbenicillin
• Smaller doses required compared to carbenicillin
• More effective against P. aeruginosa
• Fewer side effects
• Can be administered with clavulanic acid

72
Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins

• Administered by injection
• Generally more active than carboxypenicillins vs.
  streptococci and Haemophilus species
• Generally have similar activity vs Gram -ve
  aerobic rods
• Generally more active vs other Gram -ve bacteria
• Azlocillin is effective vs P. aeruginosa
• Piperacillin can be administered alongside
  tazobactam

73
The Extended Spectrum Penicillins include
Piperacillin and Ticarcillin (parenteral) as well
as Carbenicillin (oral)
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci
Gram-negative bacteria Neisseria meningitidis, Some Haemophilus influenzae, Some Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria Clostridia spp. (except C. difficile), Some Bacteroides spp.
74
Extended-Spectrum Penicillin b-Lactamase
Inhibitor Combinations includePiperacillin-tazoba
ctam as well as ticarcillin-clavulanate (both
pairs are parenteral)
Gram-positive bacteria Some Staphylococcus aureus, Streptocosoccus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria Neisseria spp. Haemophilus influenzae, Most Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria Clostridia spp. (except C. difficile), Bacteroides spp.
75
CEPHALOSPORINS
76
1. Introduction

• Antibacterial agents which inhibit bacterial cell
  wall synthesis
• Discovered from a fungal colony in Sardinian
  sewer water (1948)
• Cephalosporin C identified in 1961

77
6. Mechanism of Action

• The acetoxy group acts as a good leaving group
  and aids the mechanism

78
The Cephalosporins
Generation Parenteral Agents Oral Agents
First-generation Cefazolin Cefadroxil, cephalexin
Second-generation Cefotetan, cefoxitin, cefuroxime Cefaclor, cefprozil, cefuroxime axetil, loracarbef
Third-generation Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime
Fourth-generation Cefepime
79
8. First Generation Cephalosporins
Cephalothin

• First generation cephalosporin
• More active than penicillin G vs. some Gram -ve
  bacteria
• Less likely to cause allergic reactions
• Useful vs. penicillinase producing strains of S.
  aureus
• Not active vs. Pseudonomas aeruginosa
• Poorly absorbed from GIT
• Administered by injection
• Metabolised to give a free 3-hydroxymethyl group
  (deacetylation)
• Metabolite is less active

80
8. First Generation Cephalosporins
Cephalothin - drug metabolism
Less active OH is a poorer leaving group

• Strategy
• Replace the acetoxy group with a metabolically
  stable leaving group

81
8. First Generation Cephalosporins
Cephaloridine

• The pyridine ring is stable to metabolism
• The pyridine ring is a good leaving group
  (neutralisation of charge)
• Exists as a zwitterion and is soluble in water
• Poorly absorbed through the gut wall
• Administered by injection

82
8. First Generation Cephalosporins
Cefalexin

• The methyl group at position 3 is not a good
  leaving group
• The methyl group is bad for activity but aids
  oral absorption - mechanism unknown
• Cefalexin can be administered orally
• A hydrophilic amino group at the a-carbon of the
  side chain helps to compensate for the loss of
  activity due to the methyl group

83
First Generation Cephalosporins
Cefazolin
Cefadroxil
Cefalexin
84
First Generation Cephalosporins include Cefazolin
(parenteral) as well as cefadroxil and cephalexin
(oral).
Gram-positive bacteria Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae
Gram-negative bacteria Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis
85
9. Second Generation Cephalosporins
9.1 Cephamycins
Cephamycin C

• Isolated from a culture of Streptomyces
  clavuligerus
• First b-lactam to be isolated from a bacterial
  source
• Modifications carried out on the 7-acylamino side
  chain

86
9. Second Generation Cephalosporins
9.1 Cephamycins
Cefoxitin

• Broader spectrum of activity than most first
  generation cephalosporins
• Greater resistance to b-lactamase enzymes
• The 7-methoxy group may act as a steric shield
• The urethane group is stable to metabolism
  compared to the ester
• Introducing a methoxy group to the equivalent
  position of penicillins (position 6) eliminates
  activity.

87
9. Second Generation Cephalosporins 9.2
Oximinocephalosporins
Cefuroxime

• Much greater stability against some b-lactamases
• Resistant to esterases due to the urethane group
• Wide spectrum of activity
• Useful against organisms that have gained
  resistance to penicillin
• Not active against P. aeruginosa
• Used clinically against respiratory infections

88

• Second generation
• The second-generation cephalosporins have a
  greater Gram-negative spectrum while retaining
  some activity against Gram-positive cocci. They
  are also more resistant to beta-lactamase.
• Cefaclor (Ceclor, Distaclor, Keflor, Raniclor)
• Cefonicid (Monocid)
• Cefprozil (cefproxil Cefzil)
• Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym)
  
• Cefuzonam

89
Forms of Cefuroxime (2nd generation
cephalosporin)
Cefuroxime (ZINACEF)
Cefuroxime axetil (CEFTIN)
90
The Second-generation cephalosporins include
Cefotetan, cefoxitin, and cefuroxime (all
parenteral) as well as Cefaclor, cefprozil,
cefuroxime axetil, and loracarbef (all oral).
Gram-positive bacteria True cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp.
Anaerobic bacteria Cefoxitin and cefotetan have moderate anaerobic activity.
91
10. Third Generation Cephalosporins
Oximinocephalosporins

• Aminothiazole ring enhances penetration of
  cephalosporins across the outer membrane of Gram
  -ve bacteria
• May also increase affinity for the
  transpeptidase enzyme
• Good activity against Gram -ve bacteria
• Variable activity against Gram ve cocci
• Variable activity vs. P. aeruginosa
• Lack activity vs MRSA
• Generally reserved for troublesome infections

92
10. Third Generation Cephalosporins
Oximinocephalosporins
Ceftazidime

• Injectable cephalosporin
• Excellent activity vs. P. aeruginosa and other
  Gram -ve bacteria
• Can cross the blood brain barrier
• Used to treat meningitis

93
The Third-generation Cephalosporins include
Cefotaxime, ceftazidime, ceftizoxime, and
ceftriaxone (all parenteral) as well as Cefdinir,
cefditoren, cefpodoxime proxetil, ceftibuten, and
cefixime (all oral).
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae, Modest activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Some Enterobacteriaceae.
Anaerobic bacteria
Atypical bacteria
Spirochetes Borrelia burgorferi
94
11. Fourth Generation Cephalosporins
Oximinocephalosporins

• Zwitterionic compounds
• Enhanced ability to cross the outer membrane of
  Gram negative bacteria
• Good affinity for the transpeptidase enzyme
• Low affinity for some b-lactamases
• Active vs. Gram ve cocci and a broad array of
  Gram -ve bacteria
• Active vs. P. aeruginosa

95
Fourth Generation Cephalosporins include cefepime
(parenteral).
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptocossus pneumoniae. Modest activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeruginosa.
Anaerobic bacteria
Atypical bacteria
96
Newer b-Lactam Antibiotics
Thienamycin (Merck 1976)(from Streptomyces
cattleya)

• Potent and wide range of activity vs Gram ve and
  Gram -ve bacteria
• Active vs. Pseudomonas aeruginosa
• Low toxicity
• High resistance to b-lactamases
• Poor stability in solution (ten times less stable
  than Pen G)

97
Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
98
The Carbapenems include Imipenem/cilstatin,
Meropenem, and Ertapenem (all parenteral)
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Modest activity against Staphylococcus aureus, Some enterococci, Listeria monocytogenes
Gram-negative bacteria Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria Bacteroides fragilis, Most other anaerobes.
99
Newer b-Lactam Antibiotics
Clinically useful monobactam

• Administered by intravenous injection
• Can be used for patients with allergies to
  penicillins
• and cephalosporins
• No activity vs. Gram ve or anaerobic bacteria
• Active vs. Gram -ve aerobic bacteria

100
The Monobactams include only Aztreonam, which is
parenteral
Gram-positive bacteria
Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Most Enterobacteriaceae, Many Pseudomonas aeruginosa.
Anaerobic bacteria
Atypical bacteria
101
Vancomycin
102
Mechanism of Action of Vancomycin
Vancomycin binds to the D-alanyl-D-alanine
dipeptide on the peptide side chain of newly
synthesized peptidoglycan subunits, preventing
them from being incorporated into the cell wall
by penicillin-binding proteins (PBPs). In many
vancomycin-resistant strains of enterococci, the
D-alanyl-D-alanine dipeptide is replaced with
D-alanyl-D-lactate, which is not recognized by
vancomycin. Thus, the peptidoglycan subunit is
appropriately incorporated into the cell wall.
103

• http//student.ccbcmd.edu/courses/bio141/lecguide/
  unit2/control/vanres.html

104
Antimicrobial Activity of Vancomycin
Gram-positive bacteria Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria Clostridium spp. Other Gram-positive anaerobes.
Atypical bacteria
105
Daptomycin

• Daptomycin is a lipopeptide antibiotic
• Approved for use in 2003
• Lipid portion inserts into the bacterial
  cytoplasmic membrane where it forms an
  ion-conducting channel.

106
Antimicrobial Activity of Daptomycin
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.
Gram-negative bacteria
Anaerobic bacteria Some Clostridium spp.
Atypical
107
Rifamycins

• Rifampin is the oldest and most widely used of
  the rifamycins
• Rifampin is also the most potent inducer of the
  cytochrome P450 system
• Therefore, Rifabutin is favored over rifampin in
  individual who are simultaneously being treated
  for tuberculosis and HIV infection, since it will
  not result in oxidation of the antiviral drugs
  the patient is taking
• Rifaximin is a poorly absorbed rifamycin that is
  used for treatment of travelers diarrhea.

108
The Rifamycins include Rifampin, Rifabutin,
Rifapentine, and Rifaximin, all of which can be
administered orally. Rifampin can also be
administered parenterally.
Gram-positive bacteria Staphylococci
Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis
Anaerobic bacteria
Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacteriumleprae.
109
Aminoglycosides
The structure of the aminoglycoside amikacin.
Features of aminoglycosides include amino sugars
bound by glycosidic linkages to a relatively
conserved six-membered ring that itself contains
amino group substituents.
110

• Bacterial resistance to aminoglycosides occurs
  via one of three mechanisms that prevent the
  normal binding of the antibiotic to its ribosomal
  target
• Efflux pumps prevent accumulation of the
  aminoglycoside in the cytosol of the bacterium.
• Modification of the aminoglycoside prevents
  binding to the ribosome.
• Mutations within the ribosome prevent
  aminoglycoside binding.

111
The Aminoglycosides include Streptomycin,
Gentamicin, Tobramycin, and Amikacin (all
parenteral), as well as Neomycin (oral).
Gram-positive bacteria Used synergistically against some Staphylococci, Streptococci, Enterococci, and Listeria monocytogenes
Gram-negative bacteria Haemophilus influenzae, Enterobacteiaceae, Pseudomonas aeruginosa
Anaerobic bacteria
Atypical bacteria
Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex.
112
Macrolides and Ketolides
The structures of erythromycin and telithromycin
Circled substituents and distinguish
telithromycin from the macrolides. Substituent
allows telithromycin to bind to a second site on
the bacterial ribosome.
113
The macrolide group consists of Erythromycin,
Clarithromycin, and Azithromycin (all oral, with
erythromycin and azithromycin also being
available parenterally).
Gram-positive bacteria Some Streptococcus pyogenes. Some viridans streptococci, Some Streptococcus pneumoniae. Some Staphylococcus aureus.
Gram-negative bacteria Neiseria spp. Some Haemophilus influenzae. Bordetella pertussis
Anaerobic bacteria
Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila, Some Rickettsia spp.
Mycobacteria Mycobacterium avium complex, Mycobacterium leprae.
Spirochetes Treponema pallidum, Borrelia burgdorferi.
114
The related ketolide class consists of
Telithromycin (oral).
Gram-positive bacteria Streptococcus pyogenes, Streptococcus pneumoniae, Some Staphylococcus aureus
Gram-negative bacteria Some Haemophilus influenzae, Bordetella pertussis
Anaerobic bacteria
Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila
115
The Tetracycline Antibiotics
The structure of tetracycline
116
The Tetracycline Class of Antibiotics consists of
Doxycycline and Tigecycline (parenteral) as well
as Tetracycline, Doxycycline and Minocycline
(oral)
Gram-positive bacteria Some Streptococcus pneumoniae
Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis
Anaerobic bacteria Some Clostridia spp. Borrelia burgdorferi, Treponema pallidum
Atypical bacteria Rickettsia spp. Chlamydia spp.
117
Tigecycline
118
The antimicrobial activity of Tigecycline
(parenteral)
Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci, Listeria monocytogenes
Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Enterobacteriaceae
Anaerobic bacteria Bacteroides fragilis, Many other anaerobes
Atypical bacteria Mycoplasma spp.
119
Chloramphenicol
120
The Antimicrobial Activity of Chloramphenicol
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci. Some Streptococcus pneumoniae
Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Salmonella spp. Shigella spp.
Anaerobic bacteria Bacteroides fragilis. Some Clostridia spp. Other anaerobic Gram-positive and Gram negative bacteria
Atypical bacteria Rickettsia spp. Chlamydia trachomatis, Mycoplasma spp.
121
Clindamycin
122
The Antimicrobial Activity of Clindamycin (both
oral and parenteral)
Gram-positive bacteria Some Streptococcus pyogenes, Some viridans group streptococci. Some Streptococcus pneumoniae, Some Staphylococcus aureus
Gram-negative bacteria
Anaerobic bacteria Some Bacteroides fragilis, Some Clostridium spp. Most other anaerobes.
Atypical bacteria
123
Streptogramins
124
The Antimicrobial Activity of Quinupristin/Dalfopr
istin (parenteral)
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria
125
The Oxazolidinones
The structure of Linezolide
126
The Antimicrobial Activity of Linezolid (both
oral and parenteral)
Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria
127
The related ketolide class consists of
Telithromycin (oral).
Gram-positive bacteria
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria
128
The related ketolide class consists of
Telithromycin (oral).
Gram-positive bacteria
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria