Antibiotics/ Chemotherapeutic agents

1. Inhibition of Cell Wall Synthesis

• Most bacterial cell walls contain a rigid girdle of peptidoglycan.
• Penicillin and cephalosporin block synthesis of peptidoglycan, causing
the cell wall to lyse.
• Penicillins do not penetrate the outer membrane and are less effective
against Gram-negative bacteria.
• However, broad spectrum penicillins and cephalosporins can cross the
outer membranes of Gram-negative bacteria.
 Penicillin: Mechanism of Action

• Inhibit bacterial growth by interfering with

transpeptidation reaction of bacterial
cell wall synthesis
(cell wall is unique to bacteria made up of
polymers of polysaccharides, polypeptides,
peptidoglycans)
Penicillin: Mechanism of Action

• 3 Steps
1.Drug binds to specific receptors called
penicillin-binding proteins (PBP) in
the cytoplasmic membrane
2.Inhibition of transpeptidase (enzyme
which inhibits cross-link formation)
3. Activation of autolytic enzymes
Beta Lactams Against Bacterial Cell Wall

Cell wall
Osmotic
Pressure

Cell Membrane

Antibiotic against cell wall

Osmotic
Pressure
Cell membrane rupture in
hypotonic environment
2. Disruption of cell membrane
 Injury to the Plasma Membrane
• A cell with a damaged membrane
dies from a disruption in
metabolism or lysis.
• These drugs have specificity for a
particular microbial group, based on
differences in types of lipids in their
cell membranes.
• Polymyxins interact with
phospholipids and cause leakage,
particularly in gram-negative
bacteria
• Polymyxin B (against Gram
negatives)
– Topical
– Combined with Bacitracin
and Neomycin (broad spectrum)
3. Inhibition of Protein Synthesis
Protein Synthesis Inhibitors
 Drugs That Block Protein Synthesis
• Streptomycin inserts on sites on the 30S subunit and cause misreading of
mRNA.
• Tetracyclines block attachment of tRNA on the A acceptor site and stop
further synthesis.
Tetracycline

• Broad-spectrum, block protein synthesis (blocks attachment of

tRNA)

• Low cost

• Doxycycline & minocycline – oral drugs taken for STDs, Rocky

Mountain spotted fever, Lyme disease, typhus, acne & protozoa
4. Inhibition of Nucleic Acid Synthesis
 Inhibitors of Nucleic Acid Synthesis
• Rifamycins (Rifampin)
– Inhibits RNA synthesis (transcription)
– Leprosy, Tuberculosis,

• Quinolones
– Ciprofloxacin (cipro)
– Inhibits DNA gyrase (causes negative supercoiling of the DNA in
replication)
– Wide applications (including respiratory and urinary tract infections,
anthrax)
5. Inhibition of synthesis of
metabolites
 Competitive Inhibitors
– Sulfonamides (Sulfa drugs) and Trimithoprim
• block enzymes required for tetrahydrofolate
synthesis needed for DNA & RNA synthesis.
• Inhibit folic acid synthesis
• Broad spectrum

ACTION OF ENZYME INHIBITORS

Emergence of Antibiotic
Resistance
 Antibiotic Resistant Bacteria
Are:

• Bacteria that mutate and are able to resist the

antibiotics that are meant to kill them.
• This is a normal process speeded up by the
overuse and misuse of antibiotics.
 Why is Antibiotic Misuse a
Problem?
• Antibiotics become less effective and may not
work the next time you use them.
• Improper use of antibiotics leads to more
antibiotic resistant bacteria.
• Antibiotic resistant bacteria can be spread
throughout the community and from person
to person.
 Antibiotics promote resistance

• If a patient forgets to take the doses regularly,

• Then resistant strains get a chance to build up
• The antibiotics also kill bacteria which are
non-pathogens e.g. normal flora.
• Killing of normal flora reduces the competition
for the resistant pathogens which will
proliferate quickly.
 Antibiotic Resistance in Bacteria
How does it happen ?
• Bacteria can become resistant as a
result of genetic mutations; these
can be transferred between bacteria.
• Under selection pressure of
antibiotic exposure, these strains
then proliferate.
 Selection for Antimicrobial-
Resistant Strains

Resistant Strains
Rare
Antimicrobial
Exposure

Resistant Strains
Dominant
Mechanisms of Resistance

Genetic Mechanisms

Non-Genetic Mechanisms
Genetic Mechanisms
Chromosome-mediated
• Due to spontaneous mutation:
• in the target molecule
• in the drug uptake system
Plasmid-mediated
• Common in Gram-negative rods
• Transferred via conjugation
• Multidrug resistance
Transposon-mediated
 Non-Genetic Mechanism

Inaccessibility to drugs (e.g., abscess, TB

lesion)

Stationary phase (insusceptible to inhibitors

of cell wall synthesis)

Protoplasts and spheroplasts (insusceptible

to inhibitors of cell wall synthesis)
Resistance Mechanisms
 Inactivation of drug

S. aureus, Haemophilus sp., E. coli,

Pseudomonas aeruginosa,
Enterobacter sp.

Many kinds of β-lactamases produced

with different spectrums
Penicillin: Resistance

β- lactamase enzyme