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Antibiotics; Inhibitors of Cell Wall Synthesis
LECTURE 22:
Microbiology and Virology; 3 Credit hours
Atta-ur-Rahman School of Applied Biosciences (ASAB)National University of Sciences and Technology (NUST)
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Antibiotics
• Antibiotics are agents that are "selectively" toxic for bacteria (either killing them [bactericidal] or inhibiting their growth [bacteriostatic]) without harm to the patient.
• Antibiotics work most efficiently in conjunction with an active immune system to kill infecting bacteria in the host.
• The minimal inhibitory concentration (MIC) refers to the lowest concentration of an antibiotic that stops visible growth.
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Components of Cell Wall
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Peptidoglycan
• Peptidoglycan consists of polysaccharide backbone consisting of N-acetyl muramic acid and N-acetyl glucosamine with peptide side chains containing D- and L- amino acids and in some instances diaminopimelic acid.
• The side chains are cross-linked by peptide bridges by Penicillin binding protein (PBP).
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Synthesis of Cell Wall• The precursor subunit (muramyl
pentapeptide attached to uridine diphosphate, UDP) is synthesized in the cytoplasm and passed to the cell membrane.
• The subunit is moved enzymatically to a lipid carrier (undecaprenol) and built into a completed subunit (disaccharide pentapeptide with attached bridge peptide).
• The completed subunits are then exported to the cell wall.
• After release of the monomer the undecaprenol is recirculated in the cell membrane and used again.
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Synthesis of Cell Wall• The glycan backbones of
the existing cell wall is enzymatically broken (by autolysins) to allow insertion of the newly synthesized subunit.
• Cross-linking of the peptide side-chain of the inserted subunit to the existing chain then occurs enzymatically (penicillin binding proteins).
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Synthesis of Lipopolysaccharide• Lipid A is assembled in the
cell membrane and the core sugars attached sequentially.
• O-antigen subunits are independently synthesized (on a lipid carrier as in peptidoglycan synthesis).
• The fully synthesized O-antigen is then attached to the lipid A-core (generating lipopolysaccharide) in the cell membrane before insertion into the outer membrane.
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Antibiotics; Mechanism
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1- Cycloserine; Inhibition of peptidoglycan synthesis
• The terminal two amino acids of a peptide side chain of peptidoglycan are unusual amino acids (D-alanine as opposed to its isomer L-alanine).
• The antibiotic cycloserine is an analog of D-alanine and interferes with enzymatic conversion of L-alanine to D-alanine in the cytoplasm.
• Thus, subsequent synthesis of peptidoglycan cannot occur.
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Cycloserine; Antibiotic
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2- Vancomycin; Inhibition of peptidoglycan synthesis
• Cross-linking of the peptide occurs in the cell wall.
• During this process D-alanine is enzymatically excised from the end of a pre-existing peptide side chain allowing it to be cross-linked (by a new peptide bond) to the recently synthesized peptidoglycan subunit.
• Vancomycin binds to D-alanine-D-alanine thus sterically inhibits transpeptidation (cross-linking).
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Vancomycin
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3- β-Lactam; Inhibition of peptidoglycan synthesis
• The beta lactam antibiotics include penicillins (e.g. ampicillin), cephalosporins and monobactams and carbapenems.
• They bind to and inhibit enzymes (penicillin binding proteins) involved in the transpeptidation (cross-linking) of peptidoglycan.
• These antibiotics have in common the four membered lactam ring.
• Attached to the lactam, penicillins have an additional five membered ring and cephalosporins a six membered ring.
• Monobactams consist of the lactam ring alone and display antibiotic activity.
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β-Lactam Antibiotics
Penicillin nucleusBenzyl penicillin
Monobactam nucleusAmpicillinAztreonm
Carbapenem nucleusImipenem
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4- Bacitracin; Inhibition of peptidoglycan synthesis
• The peptidoglycan subunit is passed across the cytoplasmic membrane attached to undecaprenol diphosphate.
• After the nascent peptidoglycan monomer leaves the carrier on reaching the cell wall, the undecaprenol diphosphate is dephosphorylated to its monophosphate form.
• Bacitracin inhibits the dephosphorylation reaction and in the absence of monophosphorylated carrier peptidoglycan subunit synthesis stops.
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Bacitracin
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5- Polymyxin B ; Inhibition of peptidoglycan synthesis
• It is derived from the bacterium Bacillus polymyxa.• Polymyxin B binds to the lipid A portion of
lipopolysaccharide and also to phospholipids. However, it binds preferentially to lipid A. This disrupts the outer membrane of Gram negative bacteria.
• Since the cell membrane is not exposed in Gram positive bacteria polymyxin has little activity against them.
• This drug is toxic to human cells, since it can also lyze eukaryotic membranes; this explains its limited clinical use.