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Antimicrobial
agents and chemotherapy
p. 473-511
Introduction
p
Interaction
between host, microbial pathogen, and antimicrobial agent
(Fig 33.1)
Selective toxicity
p
Antimicrobial
agent require selective toxicity
n
inhibits or
kills microbial pathogen
n
Has little or
no toxic effect on host
n
Targets site in
pathogen is absent or different from host cell
p
Desirable
features of ideal antimicrobial agents (Fig 33.3)
Discovery and design of
antimicrobial drugs
p
Antimicrobial
agents are:
n
Natural
products
n
Semi-synthetic
n
Entirely
synthetic
p
Discovered by:
n
Chance
n
Screening of
soil microbes
n
Genomic
approaches
n
Rational design
of an antimicrobial agent (Fig 33.4)
Classification of
antibacterial agents
p
3 ways:
–
Bactericidal or bacteriostatic
–
By target site (5 sites of action)
•
Cell wall synthesis
•
Protein synthesis
•
Nucleic acid synthesis
•
Metabolic pathways
•
Cell membrane function
–
By chemical structure
Resistance to
antibacterial agents
p
Innate resistance
n
Lack susceptible target or impermeable to
agents
p
Acquired resistance (fig 33.6)
n
Chromosomal mutation
n
Transmissible plasmids
n
Transposons
n
Integrons
Mechanisms of resistance
p
3 types
–
Target site is
altered
–
Access to
target site is altered
–
Decreases drug
reaching target site
–
Destruction of
antibacterial agent (drug inactivation)
–
Involves enzymes
–
Beta-lactamases
–
Aminoglycosides-modifying
enzymes
–
Chloramphenicol
acetyl transferases
Classes of antibacterial agents
•
Inhibitors of cell wall synthesis
•
Target is peptidoglycan
p
Synthesis of peptidoglycan (Fig. 33.10)
•
Antibacterial agents:
•
Beta-lactams
•
Contain beta-lactam ring
•
Inhibit cell wall synthesis by binding to
penicillin-binding proteins (PBPs)
•
Penicillin
n
Resistance:
p
Alteration in target site
§
MRSA – makes extra PBPs
§
Alteration in access to target site
§
Production of lactamase
•
Glycopeptides
•
Large molecules, do not penetrate
Gram-negative cell wall well
•
Bactericidal
•
Vancomycin and teicoplanin
p
Active only against gram-positive bacteria
p
Use in cases of:
•
resistance to beta-lactams (MRSA)
§
Allergic reactions to beta-lactams
§
Treatment of C. difficile
•
Resistance
p
Intrinsic resistance
p
Acquired resistance
2. Inhibitors of protein synthesis
p
Selective
toxicity
Fig. 33.16
•
Aminoglycosides
•
Binds to 30S
subunit
•
Causes
misreading of mRNA codons
•
Interferes with
binding of fmet-tRNA to ribosome
•
prevent
formation of initiation complex
•
Streptomycin,
gentamycin
•
Resistance
p
Alteration of
30S subunit
p
Alterations in
cell wall permeability
p
Production of
aminoglycoside-modifying enzymes
•
Tetracycline
•
Bacteriostatic,
broad spectrum
•
penetrate cells
readily
•
binds to 30S
subunit
•
prevent
aminoacyl tRNA from entering acceptor site
•
Avoided in
pregnancy and young children
p
Suppresses
normal flora
à
overgrowth of opportunistic pathogens
p
Interference
with bone development and stains teeth
p
Liver damage
• Chloramphenicol
•
Affects 50S subunit
•
blocks action of peptidyl transferase
(prevents peptide bond formation)
•
Systemic use is limited:
p
toxic effects – bone marrow suppressant
p
resistance (chloramphenicol acetyl
transferases)
Macrolides
p
Erythromycin
n
Bacteriostatic
n
Effective against Gram-positive cocci,
mycoplasmas, chlamydiae and rickettsiae
n
Uses
p
Treatment of atypical pneumonia; chlamydial
infections
n
Binds to 50S subunit of ribosome
p
blocks translocation
n
Resistance:
p
genes encoded on plasmids for efflux
p
alteration in 50S subunit
3. Inhibitors of nucleic
acids synthesis
•
Quinolones
•
Synthetic
•
Interfere with
replication of bacterial chromosome
•
inhibit
bacterial DNA gyrase and topoisomerases
•
Nalidixic acid
•
Rifamycins
•
Rifampicin
p
blocks synthesis
of mRNA
p
Crosses
blood-brain barrier
p
Red – causes
urine, sweat and saliva to turn orange
•
Primary use
p
treatment of
mycobacterial infections, prosthetic valve endocarditis
•
Resistance:
p
chromosomal
mutation
à
alteration in RNA polymerase target
•
Antimetabolites
affecting nucleic acid synthesis
•
Produces
metabolites for nucleic acid synthesis
•
Sulfonamides
p
Structural
analogs of PABA (Fig 33.29)
p
Competes with
PABA for active site of dihydropteroate synthetase (Fig
33.30)
p
Acts against
gram-negative bacteria
p
Used in
treatment of urinary tract infections
p
Resistance is
widespread
•
Due to
plasmid-encoded altered dihydropteroate synthetase
•
Trimethroprim
p
Structural analog of aminohydroxypyrimidine
moiety of folic acid
p
Used in combination with sulfamethoxazole to
treat urinary tract infections
p
Resistance
•
Due to plasmid-encoded altered dihydrofolate
reductases
4. Inhibitors of
cytoplasmic membrane function
•
Polymyxins
•
Bactericidal
•
Disrupts phospholipid structure of cell
membrane
•
Active against Gram-negative bacteria
•
Uses:
p
Primarily topical, highly toxic, not absorbed
from gut
p
Gut decontamination
p
Wound irrigation
p
Bladder wash out
Antituberculous agents
M. tuberculosis
n
have waxy cell
wall
n
Slow growth
p
Drugs used:
n
Isoniazid
n
Ethambutol
n
Rifampicin
n
Pyrazinamide
n
Streptomycin
p
Resistance:
n
combinations of
drugs used
Antibacterial agents in practice
p
Susceptibility
tests
n
Determine drug
susceptibility of bacteria
n
Interactions
between drugs
p
2 types
n
Diffusion tests
n
Dilution tests
Disk diffusion test
E test
Dilution test
p
Quantitative estimate of susceptibility
n
MIC – lowest concentration to inhibit growth
of bacteria
n
MBC – lowest concentration required to kill
bacteria
Antibacterial agent
combinations
p
Drug interactions may be:
n
Synergistic
n
Antagonistic
p
Reasons for using drug combinations (fig
33.36)
Antiviral therapy
p
Fig 33.38
n
Antiviral drugs
p
few
p
narrow in spectrum
Fig 33.39 site of action
of antiviral agents
Interaction between host,
microbe and antimicrobial agents,
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