2. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Mechanism of action
include:
Inhibition of cell wall
synthesis
Inhibition of protein
synthesis
Inhibition of nucleic acid
synthesis
Inhibition of metabolic
pathways
Interference with cell
membrane integrity
3. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Inhibition of Cell wall synthesis
Bacteria cell wall unique in
construction
Contains peptidoglycan
Antimicrobials that interfere with
the synthesis of cell wall do not
interfere with eukaryotic cell
Due to the lack of cell wall in animal
cells and differences in cell wall in
plant cells
These drugs have very high
therapeutic index
Low toxicity with high effectiveness
Antimicrobials of this class include
β lactam drugs
Vancomycin
Bacitracin
4. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Penicillins and cephalosporins
Part of group of drugs
called β –lactams
Have shared chemical
structure called β-lactam
ring
Competitively inhibits
function of penicillin-
binding proteins
Inhibits peptide bridge
formation between glycan
molecules
This causes the cell wall
to develop weak points at
the growth sites and
become fragile.
5. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
The weakness in the cell
wall causes the cell to
lyze.
6. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
The weakness in the cell wall
causes the cell to lyze.
Penicillins and cephalosporins are
considered bactericidal.
Penicillins are more effective
against Gram+ bacteria. This is
because Gram + bacteria have
penicillin binding proteins on
their walls.
7. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
The cephalosporins
Chemical structures make them resistant to
inactivation by certain β-lactamases
Tend to have low affinity to penicillin-binding
proteins of Gram + bacteria, therefore, are most
effective against Gram – bacteria.
Chemically modified to produce family of related
compounds
First, second, third and fourth generation
cephalosporins
8. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Vancomycin
Inhibits formation of glycan chains
Inhibits formation of peptidoglycans and cell wall
construction
Does not cross lipid membrane of Gram -
Gram - organisms innately resistant
Important in treating infections caused by penicillin
resistant Gram + organisms
Must be given intravenously due to poor absorption from
intestinal tract
Acquired resistance most often due to alterations in side
chain of NAM molecule
Prevents binding of vancomycin to NAM component of glycan
9. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Bacitracin
Interferes with transport of peptidoglycan
precursors across cytoplasmic membrane
Toxicity limits use to topical applications
Common ingredient in non-prescription first-
aid ointments
10. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Inhibition of protein synthesis
Structure of prokaryotic ribosome acts as target for
many antimicrobials of this class
Differences in prokaryotic and eukaryotic ribosomes
responsible for selective toxicity
Drugs of this class include
Aminoglycosides
Tetracyclins
Macrolids
Chloramphenicol
11. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Aminoglycosides
Irreversibly binds to 30S
ribosomal subunit
Causes distortion and
malfunction of ribosome
Blocks initiation
translation
Causes misreading of
mRNA
Not effective against
anaerobes, enterococci
and streptococci
Often used in synergistic
combination with β-lactam
drugs
Allows aminoglycosides to
enter cells that are often
resistant
12. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Examples of
aminoglycosides include
Gentamicin,
streptomycin and
tobramycin
Side effects with
extended use include
Otto toxicity
Nephrotoxicity
13. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Tetracyclins
Reversibly bind 30S
ribosomal subunit
Blocks attachment of
tRNA to ribosome
Prevents continuation of
protein synthesis
Effective against certain
Gram + and Gram -
Newer tetracyclines such
as doxycycline have longer
half-life
Allows for less frequent
dosing
14. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Resistance due to
decreased accumulation
by bacterial cells
Can cause discoloration
of teeth if taken as
young child
15. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Macrolids
Reversibly binds to 50S
ribosome
Prevents continuation of
protein synthesis
Effective against variety of
Gram + organisms and
those responsible for
atypical pneumonia
Often drug of choice for
patients allergic to
penicillin
Macrolids include
Erythromycin,
clarithromycin and
azithromycin
16. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Resistance can occur
via modification of RNA
target
Other mechanisms of
resistance include
production of enzyme
that chemically
modifies drug as well
as alterations that
result in decreased
uptake of drug
17. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Chloramphenicol
Binds to 50S ribosomal
subunit
Prevents peptide bonds
from forming and
blocking proteins
synthesis
Effective against a wide
variety of organisms
Generally used as drug
of last resort for life-
threatening infections
Rare but lethal side
effect is aplastic anemia
18. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Inhibition of nucleic acid synthesis
These include
Fluoroquinolones
Rifamycins
19. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Fluoroquinolones
Inhibit action of topoisomerase DNA gyrase
Topoisomerase maintains supercoiling of DNA
Effective against Gram + and Gram -
Examples include
Ciprofloxacin and ofloxacin
Resistance due to alteration of DNA gyrase
20. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Rifamycins
Block prokaryotic RNA polymerase
Block initiation of transcription
Rifampin most widely used rifamycins
Effective against many Gram + and some Gram - as
well as members of genus Mycobacterium
Primarily used to treat tuberculosis and Hansen’s
disease as well as preventing meningitis after exposure
to N. meningitidis
Resistance due to mutation coding RNA polymerase
Resistance develops rapidly
21. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Inhibition of metabolic
pathways
Relatively few
Most useful are folate
inhibitors
Mode of actions to
inhibit the production
of folic acid
Antimicrobials in this
class include
Sulfonamides
Trimethoprim
22. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Sulfonamides
Group of related compounds
Collectively called sulfa drugs
Inhibit growth of Gram + and Gram - organisms
Through competitive inhibition of enzyme that aids in
production of folic acid
Structurally similar to para-aminobenzoic acid
Substrate in folic acid pathway
Human cells lack specific enzyme in folic acid pathway
Basis for selective toxicity
Resistance due to plasmid
Plasmid codes for enzyme that has lower affinity to drug
23. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Trimethoprim
Inhibits folic acid production
Interferes with activity of enzyme following enzyme
inhibited by sulfonamides
Often used synergistically with sulfonamide
Most common mechanism of resistance is
plasmid encoded alternative enzyme
Genes encoding resistant to sulfonamide and
trimethoprim are often carried on same plasmid
24. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Interference with cell
membrane integrity
Few damage cell
membrane
Polymixn B most common
Common ingredient in
first-aid skin ointments
Binds membrane of Gram
- cells
Alters permeability
Leads to leakage of cell
and cell death
Also bind eukaryotic cells
but to lesser extent
Limits use to topical
application
25. RESISTANCE TO
ANTIMICROBIAL DRUGS
Mechanisms of resistance
Drug inactivating enzymes
Some organisms produce
enzymes that chemically modify
drug
Penicillinase breaks β-lactam ring
of penicillin antibiotics
Alteration of target molecule
Minor structural changes in
antibiotic target can prevent
binding
Changes in ribosomal RNA prevent
macrolids from binding to
ribosomal subunits
26. SUSCEPTIBILITY OF BACTERIAL
TO ANTIMICROBIAL DRUG
Mechanisms of resistance
Decreased uptake of the drug
Alterations in porin proteins
decrease permeability of cells
Prevents certain drugs from
entering
Increased elimination of the drug
Some organisms produce efflux
pumps
Increases overall capacity of
organism to eliminate drug
Enables organism to resist
higher concentrations of
drug
Tetracycline resistance
28. SUSCEPTIBILITY OF BACTERIAL
TO ANTIMICROBIAL DRUG
Conventional disc diffusion
method
Kirby-Bauer disc diffusion
routinely used to
qualitatively determine
susceptibility
Standard concentration of Clear zone of inhibition
strain uniformly spread of
around disc reflects
standard media
susceptibility
Discs impregnated with
specific concentration of
Based on size of zone
antibiotic placed on plate organism can be
and incubated described as susceptible
or resistant
29. EFFECTS OF
COMBINATIONS OF DRUGS
Sometimes the chemotherapeutic effects of
two drugs given simultaneously is greater than
the effect of either given alone.
This is called synergism. For example,
penicillin and streptomycin in the treatment
of bacterial endocarditis. Damage to
bacterial cell walls by penicillin makes it
easier for streptomycin to enter.
30. EFFECTS OF
COMBINATIONS OF DRUGS
Other combinations of drugs can be
antagonistic.
For example, the simultaneous use of penicillin
and tetracycline is often less effective than
when wither drugs is used alone. By stopping
the growth of the bacteria, the
bacteriostatic drug tetracycline interferes
with the action of penicillin, which requires
bacterial growth.
31. EFFECTS OF
COMBINATIONS OF DRUGS
Combinations of antimicrobial drugs should
be used only for:
1. To prevent or minimize the emergence of
resistant strains.
2. To take advantage of the synergistic effect.
3. To lessen the toxicity of individual drugs.