1. Dr.Wafaa Ezz
Elarab
Antimicrobial Drugs-3

2. 3. Inhibitors of Nucleic Acid Synthesis
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3. 3. Inhibition of nucleic acid synthesis
Acting on DNA replication
Quinolones
Metronidazole
 Acting on RNA synthesis
Rifampin
Rifabutin

4. Inhibitors of RNA Synthesis
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Selectivity due to differences between prokaryotic and eukaryotic
RNA polymerase

5. Rifampin, Rifamycin, Rifampicin,
Rifabutin (bactericidal)
• Mode of action - These antimicrobials bind to
DNA-dependent RNA polymerase and inhibit
initiation of mRNA synthesis.
• Spectrum of activity - Broad spectrum but is
used most commonly in the treatment of
tuberculosis
• Resistance - Common
• Combination therapy - Since resistance is
common, rifampin is usually used in combination
therapy.

6. Inhibitors of DNA Synthesis
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Selectivity due to differences between prokaryotic and eukaryotic
enzymes

7. Quinolones (bactericidal)
nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin,
levofloxacin, lomefloxacin, sparfloxacin
• Mode of action - Synthetic inhibitors of DNA-Gyrase (=
Topoisomerase II), a bacterial enzyme that winds and unwinds
DNA (required for supercoiling the bacterial genome) => inhibition
of DNA synthesis and transcription
• Spectrum of activity - Gram-positive cocci and urinary tract
infections
• Resistance - Common for nalidixic acid; developing for ciprofloxacin

8. III. Mitronidazole:
• Uses: It is antiprotozoal drug but also has antibacterial
effects on anaerobic bacteria causing damage of DNA.
• Increasingly, it is used as part of treatment of
Helicobacter pylori infection of the stomach and
duodenum associated with peptic ulcer disease.
• It is used also to treat a variety of dental infections,
particularly dental abscess.
Adverse effects
• Nausea, anorexia and metallic taste, ataxia
•Teratogenic if taken in the first trimester of pregnancy

9. 4. Antimetabolite Antimicrobials

10. 4. Antimetabolites
Sulfonamides √
Dapsone
Trimethoprim √
Paraaminosalicylic acid

11. Inhibitors of Folic Acid Synthesis
• Basis of Selectivity
• Review of Folic Acid
Metabolism
p-aminobenzoic acid + Pteridine
Dihydropteroic acid
Dihydrofolic acid
Tetrahydrofolic acid
Pteridine
synthetase
Dihydrofolate
synthetase
Dihydrofolate
reductase
Thymidine
Purines
Methionine
Trimethoprim
Sulfonamides

12. Sulfonamides, Sulfones (bacteriostatic)
• Mode of action - These antimicrobials are analogues of para-
aminobenzoic acid and competitively inhibit formation of
dihydropteroic acid.
• Spectrum of activity - Broad range activity against gram-
positive and gram-negative bacteria; used primarily in urinary
tract and Nocardia infections.
• Resistance - Common
• Combination therapy - The sulfonamides are used in
combination with trimethoprim; this combination blocks two
distinct steps in folic acid metabolism and prevents the
emergence of resistant strains.

13. Competitive Inhibitors
Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Figure 5.7

14. Clinical uses
• Sulfadiazine Sulfadimidine Sulfamethoxazole
Broad range activity against gram-positive
and gram-negative bacteria; used
primarily in urinary tract, infected burns,
STDs, toxoplasmosis… infections

15. Trimethoprim,
Methotrexate, Pyrimethamine
(bacteriostatic)
• Mode of action - These antimicrobials binds to
dihydrofolate reductase and inhibit formation of
tetrahydrofolic acid.
• Spectrum of activity - Broad range activity against gram-
positive and gram-negative bacteria; used primarily in
urinary tract and Nocardia infections.
• Resistance - Common
• Combination therapy - These antimicrobials are used in
combination with the sulfonamides; this combination
blocks two distinct steps in folic acid metabolism and
prevents the emergence of resistant strains.

16. 5- Drugs that disrupt cell membrane
function
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17. Antibacterial medications that
Injure Plasma Membrane
•Polymyxin B: binds to membrane of G-
bacteria and alters permeability
•This leads to leakage of cellular contents and
cell death
•These drugs also bind to eukaryotic cells to
some extent, which limits their use to topical
applications

18. The antimicrobial agent should act at a target site which
is present in the infecting organism but absent from
host cells. This is more likely to be achievable in
prokaryotes than eukaryotes, as they are structurally
more distinct from host cells.
Examples:
a- Cell wall synthesis inhibitor is selective toxic for
bacteria this is because peptidoglycan , a vital
component of the bacterial cell wall, is compound unique
to bacteria and thus provides an optimum target for
selective toxicity.
Selective toxicity of antimicrobial agents.
Selective toxicity of antimicrobial agents.

19. b- Tetracyclines inhibit protein synthesis by
preventing aminoacyltransfer RNA from entering the
acceptors sites on the ribosome. This action is not
selective. The selective action of tetracyclines is
based on their uptake by bacterial cells much greater
than by human cells.
c- Chloramphenicol does have some inhibitory
activity on human ribosomes and this may account
for some of the dose dependent toxicity to bone
marrow.

20. d- The selective toxicity of sulphonamides depends on
the fact that many bacteria synthesize THFA whereas
human cells lack this capacity and depend on an
exogenous supply of folic acid.
e- The selective toxicity of rifampicin is based on the far
greater affinity for bacterial polymerases than for human
enzymes.
f-The inhibition of bacterial gyrase by quinolone is
specific and does not affect the equivalent topisomerase
enzymes in mamalin cells.

21. Antimicrobial resistance
is the ability of microorganism to survive
and reproduce in the presence of
antimicrobial does that were previously
thought effective against them

22. Cross resistance
single mechanism confers
resistance to multiple
antimicrobial agents, is
commonly seen with closely
related antimicrobial agents
Cross Resistance:

23. multiple resistance
that multiple mechanisms are involved
to multiple antimicrobial agents is seen
with unrelated antimicrobial agents.
Multiple resistance

24. • The Development of Resistance in Populations
– Some pathogens are naturally resistant
– Resistance by bacteria acquired in two ways
• New mutations of chromosomal genes
• Acquisition of R-plasmids via transformation, transduction,
and conjugation.
• Mechanisms of Resistance
– At least five mechanisms of microbial resistance
1. Production of enzyme that destroys or deactivates drug
2. Slow or prevent entry of drug into the cell
3. Alter target of drug so it binds less effectively
4. Alter their metabolic chemistry
5. Pump antimicrobial drug out of the cell before it can act

25. 1- Production of enzyme that destroys or deactivates drug
2- Slow or prevent entry of drug into the cell
Decreased uptake of the drug
Alterations in porin proteins decrease permeability of
cells
Prevents certain drugs from entering

26. 3- Alter target of drug so it binds less effectively
Minor structural changes in antibiotic target can
prevent binding
Ex: Changes in ribosomal RNA prevent
aminoglycosides from binding to ribosomal
subunits
4- Alter their metabolic chemistry

27. 5- Pump antimicrobial drug out of the cell before it can act
Some organisms produce efflux pumps so increases
overall capacity of organism to eliminate drug
Enables organism to resist higher
concentrations of drug

28. Mechanism of resistance to common antimicrobial
agents
1- Betalactam
• Modification of target sites (Penicillin binding
proteins)
• Decreased accumulation (Efflux pump)
• Enzymatic inactivation (Beta-lactamase )

29. 2- Non Betalactam antibiotics
A- Vancomycin
• D-alanyl-D-alanine residue
↓
D-alanyl-D-lactate moiety
• vancomycin cannot bind to this peptide
Alter target of drug so it can not bind to the new target
B- Bacitracin
Mechanism of action: Inhibits dephosphorylation in
cycling of bactoprenol that transfers peptidoglycan
subunits to the growing cell wall
Mechanism of Resistance: Increase synthesis of the
bactoprenol molecule

30. • The loss of outer membrane porin proteins, which
involved in the penetration of polymyxin B.
• A reduction in binding of polymyxin to the cell envelope
as a result of changes in lipid and LPS composition.
3- Polymyxins
4- Aminoglycosides
• Production of aminoglycoside inactivating enzyme that
chemically modifies drug (the most common mechanism)
• Reduced uptake or decreased cell permeability:
• Altered ribosome binding Sites by mutations binding. This
mechanism is very common for streptomycin√√

31. 5- Tetracyclines
Cells become resistant to tetracycline by at least three
mechanisms:
1. Enzymatic Inactivation is the rarest type of resistance,
2. Efflux: Resistance due to decreased accumulation by
bacterial cells.
3. Ribosomal protection: through certain reactive protein
include:
- blocking tetracyclines from binding to the ribosome.
- binding to the ribosome and distorting the structure
to still allow t-RNA binding while tetracycline is bound

32. 6- Chloramphenicol
There are three mechanisms of resistance to
chloramphenicol:
• Reduced membrane permeability.
• Mutation of the 50S ribosomal subunit which lead to
structural changes in antibiotic target therefore prevent
binding.
• Production of chloramphenicol acetyltransferase which
deactivate the drug.
7- Macrolides
• Structural changes in the target ribosomal RNA.
• Production of drug-inactivating enzymes (esterases or
kinases).
• Production of active ATP-dependent efflux proteins that
transport the drug outside of the cell.

33. 8- Quinolone
Resistance due to alteration of DNA gyrase.
9- Rifamycins
Resistance due to mutation coding RNA polymerase
10- Sulfonamides and trimethoprim
Resistance due to plasmid codes for enzyme that has
lower affinity to drug

34. • Retarding Resistance
- Maintain high concentration of drug in patient for
sufficient time
• Kills all sensitive cells and inhibits others so immune
system can destroy
- Use antimicrobial agents in combination
• Synergism vs. antagonism
- Use antimicrobials only when necessary
- Develop new variations of existing drugs
Fourth generation drugs
- Search for new antibiotics, semi-synthetics, and
synthetics
Design drugs complementary to the shape of microbial
proteins to inhibit them

35. Mechanisms drug resistance
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