antibiotics lecture 03
DESCRIPTION
mechanisms of actionTRANSCRIPT
Bio 319: Antibiotics
Lecture ThreeTopic: Inhibitors of cell wall synthesis (brief)
Inhibitors of protein biosynthesis
Lecturer: Dr. G. Kattam Maiyoh
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Inhibitors of Cell Wall Synthesis
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Carbapenems
• Beta-lactam ring is fused to a 5 member ring system
• Effect on microbes and pharmacology of carbapenems similar to penicillins
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Selected Carbapenems• Imipenem– Broad spectrum including anaerobes
and Pseudomonas aeruginosa– Parentally administered– Must be combined with cilastatin to be
absorbed– Excreted by kidneys
• Meropenem, ertapenem, and doripenem are similar to imipenem but don’t need co-administration with cilastatin
cilastatin chemical compound which inhibits the human enzyme dehydropeptidase13/02/2013 4GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013
Toxicity/Contraindications of Carbapenems
• Nausea and vomiting (common)• Hypersensitivity reactions (uncommon)– Essentially the same as for penicillins, exception
is the monobactam– Cross-reactivity is possible, exception is the
monobactam
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Aztrenam – a monobactam
• Works only on Gm -ve, including Pseudomonas aeruginosa
• Useful for treating G-ve infections that require a beta-lactam because it does not elicit hypersensitivity reactions
• Monobactam - beta-lactam compounds wherein the beta-lactam ring is alone and not fused to another ring
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Beta-lactamase inhibitorsa. Clavulanic acid
– Irreversible inhibitor of β-lactamase– Good oral absorption– Combined with amoxicillin or ticarcillin
b. Sulbactam
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Peptide AntibioticsPeptide Antibiotics
Peptide Antibiotics are drugs with polypeptides structure
Sub-group of Peptide AntibioticsPolymyxinsGlycopeptidesBacitracinStreptogramins
Each drug group has its own mechanism of action4 groups and 4 mechanism
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• Peptide antibiotics – May be further classified as follows;
–Polymyxins»Polymyxin B»Colistin
–Glycopeptides»Vancomycin»Teicoplanin»Avoparcin
–Bacitracin
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PolymyxinsPolymyxinsDrug members
Polymyxin BColistin (Polymyxin E)
Mechanism of actionDetergent-like actionDamage to cell membrane functionBind to LPS and destroy outer membrane
of Gram-negative bacteriaBactericidalConcentration-dependentNon-selective on bacterial membrane
Spectrum of activityGram-negative bacteria
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PolymyxinsPolymyxins• Pharmacokinetics– Not absorbed via GI tract– If injection, drug accumulated and
slowly excreted• Toxicities– Highly toxic if systemic injection– Nephrotoxic– Neurotoxic
• Clinical uses– Oral treatment– Local treatment
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GlycopeptidesGlycopeptides• Group members– Vancomycin
• Antibacterial activity– Inhibition of cell wall synthesis– Active against Gram-positive bacteria
• Not absorbed orally, must administered IV• High toxicity– Local irritation , ototoxicity, nephrotoxicity
• Clinical uses– Hardly used in animals– Used only resistant case i.e. to beta-lactams
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BacitracinBacitracin• Only member is Bacitracin• Drug activity– Inhibit cell wall synthesis– Activity on Gram-positive bacteria– Bactericidal
• Nephrotoxic if systemic injection• Clinical uses – the same as polymyxin– Oral – as growth promoter– Local or topical drugs
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Antibiotics that Inhibit Protein Synthesis
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Protein synthesis inhibitors– Aminoglycosides– Tetracyclins_Spectinomycin– Macrolides– Chloramphenicol– Clindamycin
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Inhibition of Protein Synthesis by Antibiotics
Figure 20.413/02/2013 16GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013
Review of Initiation of Protein Synthesis
30S 1 32 GTP
1 2 3 GTP
Initiation Factors
mRNA
3
12 GTP
30S Initiation Complex
f-met-tRNA
Spectinomycin
Aminoglycosides
12
GDP + Pi 50S
70S Initiation Complex
AP
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Review of Elongation of Protein Synthesis
GTP
AP
Tu GTP Tu GDP
Ts
TsTu
+
GDPTs
Pi
P ATetracycline
AP
Erythromycin
Fusidic Acid
Chloramphenicol
G GTPG GDP + Pi
G
GDP
AP
+GTP
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Survey of Antibiotics
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Protein Synthesis Inhibitors
• Mostly bacteriostatic• Selectivity due to differences in prokaryotic
and eukaryotic ribosomes• Some toxicity - eukaryotic 70S ribosomes
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Antimicrobials that Bind to the 30S Ribosomal Subunit
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a) Aminoglycosides (bactericidal)streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical)
• Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur.
• They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. – By binding to the 16 S r-RNA the aminoglycosides increase
the affinity of the A site for t-RNA regardless of the anticodon specificity.
• May also destabilize bacterial membranes.13/02/2013 22GKM/BIO319:Antibiotics/Lec.
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Microbe Library
American Society for Microbiology
www.microbelibrary.org13/02/2013 23GKM/BIO319:Antibiotics/Lec.
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b) Aminoglycosides (bactericidal)streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical)
• Spectrum of Activity –Effective against many gram-negative and some gram-positive bacteria;
• Not useful for anaerobic (oxygen required for uptake of antibiotic) or intracellular bacteria.
• Resistance - Common• Synergy - The aminoglycosides synergize with β -lactam
antibiotics. The β -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.
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c) Tetracyclines (bacteriostatic)tetracycline, minocycline and doxycycline
• Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.
• Spectrum of activity - Broad spectrum; Useful against intracellular bacteria
• Resistance - Common
• Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.
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d) Spectinomycin (bacteriostatic)
• Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA.
• Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae
• Resistance - Rare in Neisseria gonorrhoeae
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Antimicrobials that Bind to the 50S Ribosomal Subunit
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a) Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic)
• Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity.
• Spectrum of activity - Chloramphenicol - Broad range;Lincomycin and clindamycin - Restricted range
• Resistance - Common
• Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.
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b) Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin, spiramycin
• Mode of action - The macrolides inhibit translocation.
• Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella
• Resistance - Common
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Macrolides : Macrolides : ClassificationClassification• Macrolides are drugs with lactone ring
structure• Sub-groups are based on no. of ring atom– 12-membered ring macrolides– 13-membered– 14-membered (many drugs)– 15-membered– 16-membered (many drugs)
• Special groups– Azalides – name for 15-membered– Triamilides – name for tulathromycin
(combination of 13- and 15-membered)– Ketolides – name for 14-membered with 3
keto group
MacrolidesMacrolidesDrug examples13-membered
Tulathromycin (Triamilides)14-membered
ErythromycinClarithromycin, Roxithromycin,
Dirithromycin15-membered
Azithromycin (Azalides)Tulathromycin (Triamilides)
16-memberedSpiramycinTylosin
Macrolides – general Macrolides – general propertiesproperties
• Mechanism of action– Inhibit protein
synthesis– Bind to 50S
ribosomal unit– Bacteriostatic
• Spectrum of activity– Gram-positive– Some Gram-negative– Anaerobes–Mycoplasma
Macrolides Macrolides Pharmacokinetics
Broad distribution in body tissues
High intracellular concentration
MacrolidesMacrolidesAdditional properties of
Macrolides• Anti-inflammatory effect– Inhibitory effect on
neutrophils– inhibit proinflammatory
cytokines– Useful for treatment of
inflammatory pulmonary disease
• Prokinetic effect– Stimulate movement of GI
tract
ErythromycinErythromycin
• Erythromycin is a standard or basic drug of macrolides
• Other drug members are usually compared with erythromycin
• Important adverse effect - severe diarrhea– Especially in adult horse and ruminants
• Clinical uses– Second choice (alternative drug)– Small animals– Fowls– Some cases in ruminants– Not used in pigs
Tylosin andTylosin and SpiramycinSpiramycin• Tylosin and Spiramycin– Activities are similar
to erythromycin– Good activity on
Mycoplasma• Clinical uses–Macrolides used in
ruminants and pigs– Used for Mycoplasma
infection
Advanced generation Advanced generation MacrolidesMacrolides
Example drugsRoxithromycinDirithromycinClarithromycinAzithromycin
General activity – the same as erythromycin
Better Pharmacokinetic propertiesAcid stableFewer GI side effectHigher oral availabilityLonger serum half-livesHigher tissue concentrations
KetolidesKetolides• Ketolides are 14-
membered ring macrolides with 3 keto group
• Specific drugs– Telithromycin– Cethromycin (still in
clinical study)• Important properties– Less resistance– Good activities on
bacteria resistant to erythromycin
Antimicrobials that Interfere with Elongation Factors
Selectivity due to differences in prokaryotic and eukaryotic elongation factors
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Fusidic acid (bacteriostatic)
• Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex.
• Spectrum of activity - Gram-positive cocci
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