antibiotics lecture 03

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

13/02/2013 2GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013

Carbapenems

• Beta-lactam ring is fused to a 5 member ring system

• Effect on microbes and pharmacology of carbapenems similar to penicillins


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


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


Beta-lactamase inhibitorsa. Clavulanic acid

– Irreversible inhibitor of β-lactamase– Good oral absorption– Combined with amoxicillin or ticarcillin

b. Sulbactam


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


• Peptide antibiotics – May be further classified as follows;

–Polymyxins»Polymyxin B»Colistin

–Glycopeptides»Vancomycin»Teicoplanin»Avoparcin

–Bacitracin


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


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


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


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


Antibiotics that Inhibit Protein Synthesis


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


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


Survey of Antibiotics


Protein Synthesis Inhibitors

• Mostly bacteriostatic• Selectivity due to differences in prokaryotic

and eukaryotic ribosomes• Some toxicity - eukaryotic 70S ribosomes


Antimicrobials that Bind to the 30S Ribosomal Subunit


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.

03/Sem02/2013

Microbe Library

American Society for Microbiology

www.microbelibrary.org13/02/2013 23GKM/BIO319:Antibiotics/Lec.

03/Sem02/2013

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.


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.


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


Antimicrobials that Bind to the 50S Ribosomal Subunit


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


• Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.


b) Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin, spiramycin

• Mode of action - The macrolides inhibit translocation.

• Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella



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

http://www.hiwtc.com/photo/products/20/08/63/86341.jpg

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


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


antibiotics lecture 03

Documents

cell wall synthesis

protein synthesis1

protein synthesisp

protein synthesisgkmbio319

betalactams gkmbio319

carbapenems betalactam

requirea betalactam

antibiotics lecture