Chemotherapy of Bacterial Infections
Antibiotics
Substances or chemical therapeutic agents produced by a microorganism
or a similar product produced wholly or partially by chemical synthesis
and in low concentrations inhibits the growth of or kills microorganisms
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 Have highly selective toxicity to the pathogenic
microorganisms in host body
Have no or less toxicity to the host
C
Low tendency for development of
resistance
Do not induce hyper-sensitivities
in the host
Have rapid and extensive tissue
distribution
B
A
Ideal
Antimicrobial
Drug
D
E
Be free of interactions with other drugs
F
G
Be relatively inexpensive
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Selective Toxicity
The
most
important
concept
underlying antimicrobial therapy is
selective
toxicity,
i.e;
selective
inhibition of the growth of the
microorganism without damage to the
host.
Selective toxicity is achieved by
exploiting the differences between the
metabolism and structure of the
microorganisms
and
the
corresponding features of human cells.
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 There are four major sites in the bacterial cell
that are sufficiently different from the
human cell that they serve as the basis for
the action of clinically effective drugs:




Cell wall
Ribosomes
Nucleic acids
Cell membrane
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Classification of Antibiotics
On the basis of origin
On the basis of range of activity ( spectrum of activity)
On the basis of mode of action
On the basis of effects of their activity
On the basis of route of administration
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Microbial
Bacterial, Fungal,
Actimomycetes
Synthetic
Chloramphenicol
Semi-Synthetic
Amoxycillin
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1. On the basis of Origin
• 1. Microbial- extracted from microorganisms
• Bacterial origin- Polymyxin from Bacillus polymyxa
• Fungal origin- Penicillin from Penicillium notatum
• Actimomycetes origin- Erythromycin from Streptomyces erythreus
• 2. Synthetic- synthesized in laboratories
• 3. Semi-synthetic- extracted from microorganisms and further
chemicals added by organic chemists to enhance its properties
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Anti-mycobacterial
antibiotics
A
Narrow spectrum
B
E
2. On the basis of
range of activity
Broad spectrum
D
C
Moderate spectrum
Narrow-Broad spectrum
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1.Narrow spectrum:
Active towards relatively fewer microorganisms.
Examples: macrolides, Polymyxin
2. Moderate spectrum:
Active towards Gram Positive bacteria as well as some
UTI causing Gram negative bacteria.
Examples: Aminoglycosides, Sulfonamide
3. Narrow-Broad spectrum:
Active against Gram positive and gram negative
Examples: Beta-lactum
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4. Broad spectrum:
Active against Gram positive and Gram negative
except Pseudomonas and Mycobacteria.
Examples: Chloramphenicol, Tetracycline
5. Anti-mycobacterial antibiotics:
 Active against mycobacteria.
Examples: Rifampicin
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01
BACTERICIDAL
02
BACTERIOSTATIC
Kills bacteria
Inhibits the growth
of bacteria
Penicillin
Chloramphenicol
Aminoglycosides
Macrolides
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4. On the basis of Route of Administration
1. Oral Antibiotics:
Acid stable antibiotics,
Example: Penicillin V
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2. Parenteral
Route:
Intravenous
administration
Example:Penicillin G
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Inhibitor of cell wall synthesis/
Peptidoglycan Inhibitors
B
C
Inhibitor of protein
synthesis
Inhibitor of Nucleic
acid synthesis
Inhibitor of folic acid
synthesis
E
A
D
Inhibitor of
cytoplasmic
membrane
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Detailed Antibiotic Examples
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1. Inhibition of Cell Wall Synthesis
β-Lactam Antibiotics:
 They inhibit cell wall synthesis by preventing peptide bond formation.
 These antibiotics cause pores in the cell wall which can lead to osmosis due to
excess influx of water so that cell swells or loss of water so that cell shrinks and
thus cell is burst & damaged.
 These drugs consist β-Lactam rings so called β-lactam antibiotics
 Bactericidal in nature
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1. Inhibition of Cell Wall Synthesis
Penicillin
 First antibiotic to be used clinically
 Obtained from fungus Penicillium notatum
Structure
 β-lactam is responsible for antimicrobial activity
 Properties like antimicrobial spectrum, stability to stomach acid and susceptibility to
bacterial degradative enzymes (β-lactamases) depends upon the side chain
 Also, differ in structure by the side chain
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2. Inhibition of Protein Synthesis
Protein synthesis in ribosomes
 Ribosomes in bacteria – 70s(50s
&30s);eukaryotes 80s (60S & 40S)
Drugs that act on the 30S subunit:
Aminoglycosides:
 Bactericidal in nature
 Includes gentamicin, tobramycin, streptomycin
 good coverage for Gram –ve bacilli
like E. coli
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2. Inhibition of Protein Synthesis
Inhibition Pathways:
Aminoglycosides inhibit bacterial growth via 2 pathways:
• Interfering with Translation
• Interfering with the translocation of tRNA
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1. Interfering with Translation
 Aminoglycosides inhibit translation of the mRNA by binding to
the 30S subunit of the ribosome.
 The irreversible binding of the aminoglycosides to the 30S
subunit of the ribosome causes the misreading of the codons
along the mRNA.
 This leads to improper protein expression leading to bacterial
cell death.
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2. Interfering with the translocation of tRNA
 The aminoglycosides bind irreversibly to the 30S subunit of
bacterial ribosomes.
 There is evidence that some prevent the transfer of the tRNA
from the A-site to the P-site,
 thus preventing the elongation of the polypeptide chain.
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2. Inhibition of Protein Synthesis
Drugs that act on the 50S subunit:
Macrolides:
 Bacteriostatic in nature
 Protein synthesis inhibitor
 Includes erythromycin, clarithromycin and azithromycin
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Preventing the Transfer of the tRNA from the
A-site to the P-site
 The macrolide antibiotics seem to bind at the P-site of the 50S ribosomal
subunit.
 As a result of which, during translation, the P-site is occupied by the
macrolide.
 When the t-RNA attached with the peptide chain tries to move to the P-site,
it cannot go there due to the presence of the macrolide, thus getting thrown
away.
 This prevents the transfer of the peptidyl tRNA from the A-site to the P-site
and blocks the protein synthesis due to the inhibition of the translocation of
the nascent peptide chain.
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Side Effects
 Epigastric distress
 Ototoxicity
 Cholestatic jaundice
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3. Inhibition of Nucleic Acid Synthesis
Fluoroquinolones:
 Inhibit bacterial DNA synthesis
 Are synthetic fluorinated analogs of quinolones
 Bactericidal in nature
Mechanism of Action of Quinolones
and Fluoroquinolones by inhibition of
DNA gyrase (DNA topoisomerase)
The unwinding of DNA in the bacteria
is done by enzymes in the bacteria
called DNA gyrase or DNA
topoisomerase
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4. Inhibition of Folic Acid Synthesis
Sulfonamides:
 These antimicrobials are analogues of paraaminobenzoic acid (PABA) and competitively
inhibit formation of dihydropteroic acid
 Bacteriostatic
The enzymes shown are the targets of
sulfonamides in the biosynthetic pathway of
tetrahydrofolate. In the presence of the
sulfonamides these enzymes get inhibited
competitively.
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5. Alteration of Cell-membrane Function
Polymyxins:
 Bind to the lipopolysaccharides in the outer membrane of Gram –ve bacteria
 It causes structural changes that increase membrane permeability
 In turn polymyxins enter in and disrupt the inner cytoplasmic membrane
 In result, cell content leakage occurs and the cell dies
 Positively charged free amino group of PMs act like cationic detergent to disrupt PL
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