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MECHANISMS OF ACTION OF ANTIBIOTICS
Mechanisms of ActionKnow the mechanism of action to the depth in summary sheets.
Know the reason for selective toxicity for each group of antibiotics.
Know whether each antibiotic is bactericidal or static.
Know resistance mechanism for beta lactams.
BACTERIOSTATIC AGENTS
Sulfonamides
Drugs inhibiting protein synthesis except aminoglycosides (macrolides, chloramphenicol, tetracyclines etc).
BACTERICIDAL AGENTSBeta lactams (penicillins, cephalosporins, imipenem)
Trimethoprim/sulfamethoxazole
Vancomycin
Fluoroquinolones
Aminoglycosides
MECHANISMS OF ACTIONInhibitors 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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Plus penicillin
Spheroplast
Emerging Spheroplast
Dividing Bacteria
Division
Growth site
Growth
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Mur NAc
X
Glycopeptide Polymer
X
Mur NAc
Glycopeptide Polymer
X
Glycopeptide Polymer
D-Alanine
Transpeptidase
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Penicillin Binding Proteins
Transpeptidases
Carboxypeptidases
Endopeptidases
PENICILLIN
AUTOLYSINSCEPHALOSPORINS AND IMIPENEM
Same mechanism of action as penicillins but bind to different binding proteins.
PENICILLINS ACTIVE VS GRAM - BACTERIA
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S
C
CC
C
C
N COOHO
CH3CH3NC
OR
Penicillinase
S
C
CC
C N COOH
CH3CH3NC
OR
OHO
Penicilloic Acid
(β-Lactamase)
COMBINATIONS WITH BETA LACTAMASE INHIBITORS
Penicillin plus a beta lactamase inhibitor.
FOSFOMYCIN
Inhibits peptidoglycan synthesis at an earlier stage than where the beta lactams act.
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VANCOMYCIN
Enzyme
Enzyme
NAG-NAM
D-ALA
L-GLU
LYS
D-ALA
D-ALA
Transpeptidase
PENICILLINS
X
NAG-NAM
D-ALA
L-GLU
LYS
D-ALA
D-ALA
Enzyme
VAN
Transglycosylase
RESISTANCE TO BETA LACTAMS
PenicillinaseBeta lactamases
RESISTANCE
Increased production of beta-lactamase (penicillinase) enzymes.
S
C
CC
C
C
N COOHO
CH3CH3NC
OR
Penicillinase
S
C
CC
C N COOH
CH3CH3NC
OR
OHO
Penicilloic Acid
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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
PolymyxinsDaptomycin
POLYMYXINS
Surface active amphipathic agents.
Interact strongly with phospholipids and disrupt the structure of cell membranes.
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DAPTOMYCIN
It binds to bacterial membranes resulting in depolarization of the, loss of membrane potential and cell death.
ANTIBIOTICS INHIBITING PROTEIN SYNTHESIS
MacrolidesClindamycinLinezolidStreptograminsChloramphenicolTetracyclinesAminoglycosides
50S
30S
Procaryotic Ribosome
70S--M.W.2,500,000
60S
40S
Eucaryotic Ribosome
80S--M.W. 4,200,000
Antibiotics binding to the 50S ribosomal subunit and inhibiting protein synthesis
Erythromycin and other macrolides
Chloramphenicol
Linezolid
Streptogramins
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Antibiotics binding to the 30S ribosomal subunit and inhibiting protein synthesis
Aminoglycosides
TetracyclinesCLEanS AT
Macrolides (Erythromycin, Azithromycin and Clarithromycin)
aa
A50S
30S
mRNA
template
Transferase site
P
Nascent polypeptide chain
MACROLIDES
TRANSLOCATION
CHLORAMPHENICOL
aa
A50S
30S
mRNA
template
Transferase site
P
Nascent polypeptide chain
Chloramphenicol
Mechanism of action of Chloramphenicol
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INITIATION
STREPTOGRAMINS
Quinupristin/Dalfopristin (30:70)
aa
50S
30S
mRNA
template
Transferase site
P
Nascent polypeptide chain
QUINUPRISTIN(MACROLIDE)
ADALFOPRISTIN
MECHANISM OF ACTION
Act synergistically to inhibit bacterial protein synthesis.
They bind to separate sites on the 50 S ribosomal subunit and form a ternary complex with the ribosome.
MECHANISM OF ACTION
Quinupristin binds at the same site as the macrolides and has a similar effect.
Dalfopristin directly blocks peptide bond formation by inhibiting peptidyl transferase.
Dalfopristin results in a conformational change in the 50S ribosome subunit.
INITIATION
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AMINOGLYCOSIDES
Bind irreversibly to the 30S subunit.
Exact mechanism of cell death is unknown.
A50S
30S
mRNA
template
Transferase site
P
Nascent polypeptide chain
Tetracycline
aa 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.
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TetracyclineATP
INCREASED EFFLUX OUT OF THE CELL ANTIBIOTICS ACTING AS ANTIMETABOLITES
Sulfonamides
Trimethoprim plus sulfamethoxazole
2HN COOH
DIHYDROPTERIDINE
PYROPHOSPHATE DERIVATIVE
DIHYDROPTEROIC ACID
DIHYDROFOLIC ACID
FOLIC ACID BIOSYNTHESIS
Glutamic Acid
2 ATP
2HN SO2NH2
Dihydropteroate
Synthetase
TRIMETHOPRIM-SULFAMETHOXAZOLE
2HN CH2 OCH3
OCH3
OCH3
80 mg TRIMETHOPRIM
O
2HN SO2NH
N CH3
400 mg SULFAMETHOXAZOLE
PABA
DIHYDROPTEROIC ACID
DIHYROFOLIC ACID
TETRAHYDROFOLIC ACID
+ Pteridine
SULFONAMIDE
TRIMETHOPRIMDihydrofolate Reductase
Dihydrofolate Synthetase
Dihydropteroate Synthetase
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Advantages of sulfonamide-trimethoprim combination
Results from multiple mechanisms.
Altered dihydropteroate synthetase.
Cross-resistance among all sulfonamides.
SULFONAMIDE-RESISTANCE
ANTIBIOTICS AFFECTING NUCLEIC ACID SYNTHESIS.
Fluoroquinolones
Metronidazole
FLUOROQUINOLONES
FLUOROQUINOLONES
DNA Gyrase (Topoisomerase II)-older quinolones
Topoisomerase IV-3rd and 4th
generation quinolones.
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Inactive End Products
Metronidazole
Metronidazole
Short lived intermediates
Inactive endproducts
DNARNAProtein
Other targets
Mechanism of action of metronidazole on an anaerobic organism
Ferredoxinreduced