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Antibiotics Step 1: How to Kill a Bacterium. What are the bacterial weak points? Specifically, which commercial antibiotics target each of these points? Target 1: The Bacterial Cell Envelope Structure of the bacterial cell envelope. Gram-positive. Gram-negative.

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step 1 how to kill a bacterium
Step 1: How to Kill a Bacterium.
  • What are the bacterial weak points?
  • Specifically, which commercial antibiotics target each of these points?
slide5

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.

antibiotics that target the bacterial cell envelope include
Antibiotics that Target the Bacterial Cell Envelope Include:
  • The b-Lactam Antibiotics
  • Vancomycin
  • Daptomycin
antibiotics that block bacterial protein production include
Antibiotics that Block Bacterial Protein Production Include:
  • Rifamycins
  • Aminoglycosides
  • Macrolides and Ketolides
  • Tetracyclines and Glycylcyclines
  • Chloramphenicol
  • Clindamycin
  • Streptogramins
  • Linezolid (member of Oxazolidinone Class)
slide13

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, 2002:314.)

slide14

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.

slide17

General Classes of Clinically Important Bacteria Include:

  • Gram-positive aerobic bacteria
  • Gram-negative aerobic bacteria
  • Anaerobic bacteria (both Gram + and -)
  • Atypical bacteria
  • Spirochetes
  • Mycobacteria
gram positive bacteria of clinical importance
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
gram negative bacteria of clinical importance
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
anaerobic bacteria of clinical importance
Anaerobic Bacteria of Clinical Importance
  • Gram-positive anaerobic bacilli
    • Clostridium difficile
    • Clostridium tetani
    • Clostridium botulinum
  • Gram-negative anaerobic bacilli
    • Bacteroides fragilis
atypical bacteria of clinical importance include
Atypical Bacteria of Clinical Importance Include:
  • Chlamydia
  • Mycoplasma
  • Legionella
  • Brucella
  • Francisella tularensis
  • Rickettsia
spirochetes of clinical importance include
Spirochetes of Clinical Importance Include:
  • Treponema pallidum
  • Borrelia burgdorferi
  • Leptospira interrogans
mycobacteria of clinical importance include
Mycobacteria of Clinical Importance Include:
  • Mycobacterium tuberculosis
  • Mycobacterium avium
  • Mycobacterium leprae
slide26

Mechanism of action of β-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 β-lactam antibiotic, this process is disrupted. The β-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.

slide27

Mechanism of penicillin-binding protein (PBP) inhibition by β-lactam antibiotics. PBPs recognize and catalyze the peptide bond between two alanine subunits of the peptidoglycan peptide side chain. The β-lactam ring mimics this peptide bond. Thus, the PBPs attempt to catalyze the β-lactam ring, resulting in inactivation of the PBPs.

slide28

Six P's by which the action of β-lactams may be blocked:

  • penetration,
  • porins,
  • pumps,
  • penicillinases (β-lactamases),
  • penicillin-binding proteins (PBPs), and
  • peptidoglycan.
slide31

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
slide32

http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/Spencer/spencer_cellwall.htmlhttp://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/Spencer/spencer_cellwall.html

slide33

R =

6-Aminopenicillanic acid

(6-APA)

Benzyl penicillin (Pen G)

R =

Acyl side

chain

Thiazolidine

ring

Phenoxymethyl penicillin (Pen V)

b-Lactam

ring

Penicillin G

present in corn steep liquor

Penicillin V

(first orally active penicillin)

STRUCTURE

Side chain varies depending on carboxylic acid present in fermentation medium

slide34

Shape of Penicillin G

Folded ‘envelope’ shape

slide35

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
slide36

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)
slide37

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 enzyme’s active site leading to irreversible inhibition

Covalent bond formed

to transpeptidase enzyme

Irreversible inhibition

slide38

NAM

NAM

NAM

NAM

NAM

NAM

NAM

NAM

NAM

NAG

NAG

NAG

NAG

NAG

NAG

L-Ala

L-Ala

L-Ala

L-Ala

L-Ala

L-Ala

L-Ala

L-Ala

L-Ala

D-Glu

D-Glu

D-Glu

D-Glu

D-Glu

D-Glu

D-Glu

D-Glu

D-Glu

L-Lys

L-Lys

L-Lys

L-Lys

L-Lys

L-Lys

L-Lys

L-Lys

L-Lys

Bond formation

inhibited by

penicillin

Mechanism of action - bacterial cell wall synthesis

slide39

Cross linking

Mechanism of action - bacterial cell wall synthesis

slide40

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
slide41

Normal Mechanism

Mechanism of action - bacterial cell wall synthesis

Alternative theory- Pencillin mimics D-Ala-D-Ala.

slide42

Mechanism inhibited by penicillin

Mechanism of action - bacterial cell wall synthesis

Alternative theory- Penicillin mimics D-Ala-D-Ala.

slide43

Penicillin

Acyl-D-Ala-D-Ala

Mechanism of action - bacterial cell wall synthesis

Penicillin can be seen to mimic acyl-D-Ala-D-Ala

slide44

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
slide45

Penicillin acylase

or chemical hydrolysis

Fermentation

Semi-synthetic penicillins

Penicillin Analogues - Preparation

slide46

Penicillin Analogues - Preparation

Problem - How does one hydrolyse the side chain by chemical means in presence of a labileb-lactam ring?

Answer - Activate the side chain first to make it more reactive

Note - Reaction with PCl5 requires involvement of nitrogen’s lone pair of electrons. Not possible for the b-lactam nitrogen.

slide47

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
slide48

Acid or

enzyme

Relieves ring strain

Problem 1 - Acid Sensitivity

Reasons for sensitivity

1) Ring Strain

slide49

Tertiary amide

Unreactive

b-Lactam

Folded ring

system

Impossibly

strained

Problem 1 - Acid Sensitivity

Reasons for sensitivity

2) Reactive b-lactam carbonyl group

Does not behave like a tertiary amide

X

  • Interaction of nitrogen’s lone pair with the carbonyl group is not possible
  • Results in a reactive carbonyl group
slide50

Further

reactions

Problem 1 - Acid Sensitivity

Reasons for sensitivity

3) Acyl Side Chain

- neighbouring group participation in the hydrolysis mechanism

slide51

Decreases

nucleophilicity

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

slide52

electronegative

oxygen

Penicillin V

(orally active)

Problem 1 - Acid Sensitivity

Examples

  • Better acid stability and orally active
  • But sensitive to b-lactamases
  • Slightly less active than Penicillin G
  • Allergy problems with some patients
  • Very successful semi-synthetic penicillins
  • e.g. ampicillin, oxacillin
slide54

b-Lactamase

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
slide55

Bulky

group

Enzyme

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)
slide56

ortho groups

important

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
slide57

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
slide58

Antistaphylococcal Penicillins include Nafcillin and Oxacillin (parenteral) as well as Dicloxacillin (oral)

slide59

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.
slide60

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
slide61

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)

slide62

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

slide63

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
slide64

PEN

PEN

H

C

OH

O

C

O

O

O

O

PEN

C

C

O

O

C

C

H

H

C

M

e

2

2

3

O

Formaldehyde

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
slide65

The aminopenicillins include Ampicillin (parenteral) as well as

Amoxicillin and Ampicillin (both oral)

slide66

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
slide67

1

2

N

N

H

H

2

2

O

H

3

4

5

b-Lactamase Inhibitors

Clavulanic acid - mechanism of action

slide68

Sulbactam

Tazobactam

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
slide69

The aminopenicillins + b-lactamase inhibitor combinations include ampicillin-sulbactam (parenteral) and amoxicillin-clavulanate (oral)

slide70

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
slide71

TICARCILLIN

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
slide72

Class 3 - Urea group at the a-position (ureidopenicillins)

Examples

Azlocillin

Mezlocillin

Piperacillin

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
slide73

The Extended Spectrum Penicillins include Piperacillin and Ticarcillin (parenteral) as well as Carbenicillin (oral)

slide74

Extended-Spectrum Penicillin + b-Lactamase Inhibitor Combinations include:Piperacillin-tazobactam as well as ticarcillin-clavulanate (both pairs are parenteral)

slide76

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
slide77

6. Mechanism of Action

  • The acetoxy group acts as a good leaving group and aids the mechanism
slide79

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
slide80

Metabolism

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
slide81

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
slide82

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
first generation cephalosporins
First Generation Cephalosporins

Cefazolin

Cefadroxil

Cefalexin

slide84

First Generation Cephalosporins include Cefazolin (parenteral) as well as cefadroxil and cephalexin (oral).

slide85

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
slide86

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.
slide87

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
slide88
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
forms of cefuroxime 2 nd generation cephalosporin
Forms of Cefuroxime (2nd generation cephalosporin)

Cefuroxime

(ZINACEF)

Cefuroxime axetil

(CEFTIN)

slide90

The Second-generation cephalosporins include Cefotetan, cefoxitin, and cefuroxime (all parenteral) as well as Cefaclor, cefprozil, cefuroxime axetil, and loracarbef (all oral).

slide91

R

Aminothiazole

ring

10. Third Generation CephalosporinsOximinocephalosporins

  • 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
slide92

10. Third Generation CephalosporinsOximinocephalosporins

Ceftazidime

  • Injectable cephalosporin
  • Excellent activity vs. P. aeruginosa and other Gram -ve bacteria
  • Can cross the blood brain barrier
  • Used to treat meningitis
slide93

The Third-generation Cephalosporins include Cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone (all parenteral) as well as Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, and cefixime (all oral).

slide94

R

11. Fourth Generation CephalosporinsOximinocephalosporins

  • 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
slide96

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)
slide97

Imipenem

Meropenem

Ertapenem(2002)

Newer b-Lactam Antibiotics

Thienamycinanalogues used in the clinic

slide99

Aztreonam

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
mechanism of action of vancomycin
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.

slide103
http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/vanres.htmlhttp://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/vanres.html
daptomycin
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.
rifamycins
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.
slide108

The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally.

aminoglycosides
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.

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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.
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The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).

macrolides and ketolides
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.

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The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally).

the tetracycline antibiotics
The Tetracycline Antibiotics

The structure of tetracycline

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The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline (parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral)

the oxazolidinones
The Oxazolidinones

The structure of Linezolide