1. ANTIMICROBIAL DRUGS

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

27. ANTIMICROBIAL
SUSCEPTIBILITY TESTING
 Probably the most
widely used testing
method is the disk-
diffusion method, also
known as the Kirby-
Bauer test.

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.