Download Mechanisms of action of Antibiotics

MECHANISMS OF ACTION
OF ANTIBIOTICS
BACTERIOSTATIC AGENTS


Sulfonamides
Drugs inhibiting protein synthesis
except aminoglycosides
(macrolides, chloramphenicol,
tetracyclines etc).
BACTERICIDAL AGENTS

Beta lactams (penicillins, cephalosporins,
imipenem)

Trimethoprim/sulfamethoxazole

Vancomycin

Fluoroquinolones

Aminoglycosides
MECHANISMS OF ACTION

Inhibitors of cell wall synthesis

Drugs altering cell membranes

Inhibitors of protein synthesis

Antimetabolites

Inhibitors of nucleic acid synthesis.
DRUGS INHIBITING CELL
WALL SYNTHESIS

Penicillins

Cephalosporins

Imipenem

Vancomycin

Fosfomycin
β-lactams
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Dividing Bacteria
Division
Plus penicillin
Emerging Spheroplast
Growth
Growth site
Spheroplast
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Glycopeptide
Polymer
Glycopeptide
Polymer
Mur NAc
Mur NAc
Transpeptidase
Glycopeptide
Polymer
D-Alanine
Penicillin Binding Proteins
Transpeptidases
Penicillin
Carboxypeptidases
Endopeptidases
AUTOLYSINS

All Beta lactam antibiotics act by
the same mechanism
PENICILLINS ACTIVE VS
GRAM - BACTERIA
S
O
C N
R
C
C
CH3
C CH3
C
O
N
C
COOH
Penicillinase
(β-Lactamase)
R
O
C
S
N
O C
OH
C
CH3
C CH3
N
C
Penicilloic Acid
COOH
COMBINATIONS WITH BETA
LACTAMASE INHIBITORS

Penicillin plus a beta lactamase
inhibitor.
CEPHALOSPORINS AND
IMIPENEM

Same mechanism of action as
penicillins but bind to different
binding proteins.
FOSFOMYCIN

Inhibits peptidoglycan synthesis at
an earlier stage than where the
beta lactams act.
VANCOMYCIN
Transpeptidase
NAG-NAM
D-ALA
L-GLU
LYS
E
D-ALA nz
y
m
D-ALA e
PENICILLINS
X
E
nz
y
m
e
E
nz
y
m
e
NAG-NAM
D-ALA
Transglycosylase
L-GLU
LYS
VAN
D-ALA
D-ALA
RESISTANCE TO BETA
LACTAMS


Penicillinase
Beta lactamases
S
O
C N
R
C
C
CH3
C CH3
C
O
N
C
COOH
Penicillinase
R
O
C
S
N
O C
OH
C
CH3
C CH3
N
C
Penicilloic Acid
COOH
METHICILLIN
RESISTANCE

Altered PBP’s.
RESISTANCE TO OTHER BETA
LACTAM ANTIBIOTICS



Most prevalent mechanism is
hydrolysis by beta lactamases.
Cephalosporins have variable
susceptibility to βlactamases.
Some even induce formation of the
enzymes.
RESISTANCE TO
VANCOMYCIN
ANTIBIOTICS AFFECTING
CELL MEMBRANES


Polymyxins
Daptomycin
POLYMYXINS


Surface active amphipathic agents.
Interact strongly with
phospholipids and disrupt the
structure of cell membranes.
DAPTOMYCIN

Depolarizes the cell membrane
ANTIBIOTICS INHIBITING
PROTEIN SYNTHESIS







Macrolides
Clindamycin
Linezolid
Streptogramins
Chloramphenicol
Tetracyclines
Aminoglycosides
Procaryotic Ribosome
50S
30S
70S-M.W.2,500,000
Eucaryotic Ribosome
60S
40S
80S--M.W.
4,200,000
Antibiotics binding to the 50S
ribosomal subunit and
inhibiting protein synthesis

Erythromycin and other macrolides

Chloramphenicol

Linezolid

Streptogramins
Antibiotics binding to the 30S
ribosomal subunit and
inhibiting protein synthesis

Aminoglycosides

Tetracyclines
CLEanS AT
Macrolides (Erythromycin,
Azithromycin and
Clarithromycin)
Nascent polypeptide
chain
A
50S
MACROLIDES
Transferase
site
aa
mRNA
template
P
30S
TRANSLOCATION
CHLORAMPHENICOL
Chloramphenicol
Nascent polypeptide
chain
50S
A
Transferase
site
aa
mRNA
template
P
30S
Mechanism of action of Chloramphenicol
INITIATION
STREPTOGRAMINS

Quinupristin/Dalfopristin (30:70)
Nascent polypeptide
chain
50S
DALFOPRISTIN
A
QUINUPRISTIN
(MACROLIDE)
Transferase
site
aa
mRNA
template
P
30S
INITIATION
AMINOGLYCOSIDES



Bind irreversibly to the 30S
subunit.
Exact mechanism of cell death is
unknown.
Postantibiotic effect.
50S
A
aa
Nascent polypeptide
chain
Transferase
site
mRNA
template
P
30S
Tetracycline
INHIBITION OF
MITOCHONDRIAL PROTEIN
SYNTHESIS


Mitochondrial ribosome resembles
bacterial ribosome.
May account for some toxic effects
(e.g. chloramphenicol, linezolid).
RESISTANCE


Alterations in ribosomal proteins
(e.g. macrolides).
Decreased permeability to the
antibiotic.
TETRACYCLINE RESISTANCE
ATP
Tetracycline
ANTIBIOTICS ACTING AS
ANTIMETABOLITES


Sulfonamides
Trimethoprim plus
sulfamethoxazole
FOLIC ACID BIOSYNTHESIS
DIHYDROPTERIDINE
2 ATP
PYROPHOSPHATE
DERIVATIVE
Dihydropteroate
2HN
Synthetase
DIHYDROPTEROIC ACID
Glutamic Acid
DIHYDROFOLIC ACID
COOH
2HN
SO2NH2
TRIMETHOPRIMSULFAMETHOXAZOLE
2HN
CH
OCH3
OCH3
2
OCH3
80 mg TRIMETHOPRIM
2HN
SO2NH
N
O
400 mg SULFAMETHOXAZOLE
CH3
PABA
Dihydropteroate
Synthetase
+ Pteridine
SULFONAMIDE
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TRIMETHOPRIM
TETRAHYDROFOLIC ACID

Advantages of sulfonamidetrimethoprim combination
SULFONAMIDERESISTANCE



Results from multiple mechanisms.
Altered dihydropteroate
synthetase.
Cross-resistance among all
sulfonamides.
ANTIBIOTICS AFFECTING
NUCLEIC ACID SYNTHESIS.

Fluoroquinolones

Metronidazole

Rifampin
FLUOROQUINOLONES
FLUOROQUINOLONES


Gyrase (Topoisomerase I)-older
quinolones
Topoisomerase IV-3rd and 4th gen
quinolones.
FQ RESISTANCE


Changes in gyrase and
topoisomerase
Increased efflux
Metronidazole
Metronidazole
Ferredoxin
reduced
Short lived
intermediates
DNA
RNA
Protein
Other targets
Inactive end
products
Inactive End Products
Mechanism of
action of
metronidazole on
an anaerobic
organism
RIFAMPIN