3,Antibiotics that inhibit bacterial protein synthesis.ppt

‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
Hayatt University College
Course Name:-Pharmaceutical Microbiology
Dr. Salih Osman Mohammed Ahmed

ANTIBIOTICS AND CHEMOTHERAPEUTIC AGENTS
Antibiotics that inhibit bacterial protein synthesis
The synthesis of proteins in bacteria is essentially as
two-stage :-
A. Transcription stage :-
intermediate using one strand of the duplex DNA as
the template.
Transcription is the synthesis of RNA using DNA as a
template. The process is carried out by the enzyme
RNA polymerase:-
The same enzyme is responsible for the transcription
of all of the genes in a bacterial cell, including mRNA,
rRNA and transfer RNA (tRNA). The process of
transcription can be divided into a series of stages:
1. Template recognition, initiation, Primer binding.
elongation, and termination.
2. Translated into a linear sequence of peptide bond-
linked amino acids that make up the protein.

B. Translation stage :-
In this stage the decoding of the information in the
mRNA converted into an ordered arrangement of
amino acids to form a polypeptide).
The process of translation is carried out on large
ribonuclear-protein complexes called ribosomes.

Protein Synth. Inhibitors that target the ribosome
included :-
Tertracyclines.
Aminoglycosides.
Chloramphenicol.
Macrolides.
 Lincomycins.
Fusidic acid.

A number of antibiotics their antimicrobial effects by
targeting bacterial ribosomes and inhibiting bacterial
protein synthesis.
Bacterial ribosomes different structurally from
mammalian cytoplasmic ribosomes and are composed
of 30S and 50S subunits
Mammalian ribosomes have 40S and 60S subunits.
high concentrations of drugs such as chloramphenicol
or the tetracyclines may cause toxic effects as a result
of interaction with mitochondrial mammalian
ribosomes, since the structure of mitochondrial
ribosomes more closely resembles bacterial
ribosomes.

Tetracycline's
Antibiotic that Isolated from :-
several species of Streptomyces bacteria
 or produced semi-synthetically compounds.
Bacteriostatic
enter susceptible organisms via
 passive diffusion
energy-dependent transport protein mechanism.
 bind reversibly to the 30S subunit of the bacterial
ribosome.
Prevents binding of tRNA to the mRNA– ribosome
complex
They are known as broad spectrum antibiotics .

Source & Chemistry of Tetracycline's
 natural product isolated from Streptomyces
rimosus.
 Tetracycline is semi synthetic derivative of
Chlortetracycline ( isolated from Streptomyces
aureofaciens ) .

Tetracycline's Mechanism of Action :
Tetracyclines inhibitor bacteria protein synth by :-
bind reversibly to the 30S subunit of the bacterial
ribosome and prevent access of amino acid .
Prevents binding of tRNA to the mRNA– ribosome
complex
They effected the bacteria by enter , through the
hydrophilic channels formed by Porin protein of the
outer cell membrane.
via the active transport energy dependent system.

Resistance to Tetracycline :
Resistance develops due to:
 Efflux pumps
 enzymatic inactivation of the drug
 production of bacterial proteins that prevent
tetracyclines from binding to the ribosome.
Resistance to one tetracycline does not confer
universal resistance to all tetracyclines.

Tetracycline's Pharmacokinetics
Absorption:
Tetracyclines are absorbed after oral ingestion.
 Absorption of Tetracyc. is impaired after or
within ingestion of
 Dairy prod. (milk & milk products )
 Aluminum hydroxide gel
 Ca, Mg , iron & Zn salts and
Both doxycycline and minocycline are available as
oral and intravenous (IV) preparations.

Distribution :
 Widely distributed through out the body and into tissues
& secretions including urine & prostate .
 They accumulate in RE cells of liver & spleen, bone
marrow ,dentine & enamel of unerupted teeth .
It crosses the placenta & also secreted in milk .
Excretion :
Most of the Tetracyclines is excreted in the kidney ,
liver & bile .
 Excretion also occurs through feces even after the
parenteral administration
Dose -
 wide variety of Tetracyclines are available for oral ,
parenteral & topical administration .

Tetracyclines side/ effects:
GIT
gastric burning
 Nausea
 Vomiting
Diarrhea
 Esophagitis ( give drug with food ) .
Hepatic toxicity
Renal toxicity
Effects on teeth :(Children may develop permanent
brown discoloration of teeth ).
Hypersens. react. may occur

Tetracyclines Uses for
Mycoplasma . ( M. pneumonia)Mycoplasma is
smallest living org. , lacks cell wall.
Chlamydia
Non specific urethritis.
Sexually transmitted diseases.
Anthrax.
Bacillary infections included :-
Brucellosis
Cholera
Shigellosis / Salmonella
Amoebiasis
Helicobacter pylori

Susceptibility to micro organisms(Spectrum)
The tetracyclines are bacteriostatic antibiotics
effective against a wide variety of organisms,
including:-
gram-positive .
gram-negative bacteria.
protozoa.
spirochetes.
mycobacteria.
atypical species
They are commonly used in the treatment of
Actinomyces and Chlamydia infections
(doxycycline).

Effect on Intestinal Flora
Many of the Tetracyclines are incompletely
absorbed from the GIT.
That main the concentration can be effect the flora
Sensitive aerobic & anaerobic coliform micro-org.
& G- ve spore forming bacteria are suppressed
markedly.
As the fecal coliform count declines –overgrowth
of Tetracyc. resist. micro-org.s occurs particularly-
 Yeasts (esp. Candida sp.)
 Enterococci
 Proteus &
 Pseudomonas

AMINOGLYCOSIDES
Aminoglycosides are derived from either Streptomyces
sp. or Micromonospora sp.
Aminoglycosides bactericidal antibiotic and they are
many form such as :-
 streptomycin ,
kanamycin,
gentamicin,
tobramycin,
 amikacin, netilmicin,
neomycin (topical)
 Aminoglycosides are used for the treatment of serious
infections due to aerobic gram-negative bacilli.
The term “aminoglycoside” stems from their
structure—two amino sugars joined by a glycosidic
linkage to a central hexose nucleus.

AMINOGLYCOSIDES
Bind to 30S ribosomal subunit causing misreading of
the genetic code
Combined with a β-lactam antibiotic to employ a
synergistic effect, in E. faecalis and E. faecium
infective endocarditis
resistance mechanisms are aminoglycoside specific

Aminoglycosides Mechanism of action
The aminoglycosides irreversibly bind to the 16S
ribosomal RNA and freeze the 30S initiation complex
(30S-mRNA-tRNA) .
No further initiation can occur.
the ribosome became function less to completed
ribosome to misread the genetic code.
 They also slow down protein synthesis that has
already initiated and induce misreading of the
mRNA.
aminoglycosides increase the affinity of the A site for
t-RNA regardless of the anticodon specificity.
Aminoglycosides diffuse through porin channels in
the outer membrane of susceptible organisms.
The Antibiotics inhibitor protein synthesis are
generally bacteriostatic.

Aminoglycosides Pharmacokinetics
Absorption:
The highly polar, absorption after oral
administration.
 all aminoglycosides (except neomycin must be
given parenterally to achieve adequate serum
levels
 Neomycin is not given parenterally due to severe
nephrotoxicity.
It is administered topically for skin infections .

Susceptibility to microorganisms(Spectrum)
The aminoglycosides are effective for the majority
of aerobic gram negative bacilli, including those
that may be multidrug resistant, such as
 Pseudomonas aeruginosa,
 Klebsiella pneumoniae,
 Enterobacter sp.
aminoglycosides are often combined with a β-
lactam antibiotic to employ a synergistic effect,
particularly in the treatment of
 Enterococcus faecalis
Enterococcus faecium infective endocarditis.

Distribution
Due to their hydrophilicity, tissue concentrations
may be subtherapeutic, and penetration into most
body fluids is variable.
Due to low distribution into fatty tissue, the
aminoglycosides • are dosed based on lean body
mass, not actual body weight.
 Excretion
More than 90% of the parenteral aminoglycosides
are excreted unchanged in the urine

Aminoglycosides side/ effects:
The elderly‫مسن‬ are particularly susceptible to
nephrotoxicity and ototoxicity.
Ototoxicity
Nephrotoxicity
Neuromuscular paralysis
Allergic reactions

Chloramphenicol Macrolides
The macrolide antibiotics are characterized by possessing
molecular structures that contain large (12–16-membered)
lactone rings linked through glycosidic bonds with amino
sugars.
 Prototype:
Erythromycin (from streptomyces erythreus)
Semisynthetic derivatives:
clarithramycin ,
ketolides
 azithromycin
Active against:
pneumococci,
streptococci,
staphylococci,
H. Pyroli,
Ricketssia spp,
chlamydia spp

Macrolides Machoism of action
Inhibit 50S ribosomal RNA near peptidyl
transferase center, there by preventing peptide chain
elongation by blocking of polypeptide exit tunnel.
As a result, pepidyl tRNA is dissociated from the
ribosome
Resistances:
Usually plasmic encoded, reduced permeability of
membrane, active efflux, or by production of
esterases (by enterobaceriaceae) that hydrolyzes
macrolides
 Action of clindamycin and streptogramins is
related to that of erythromycin

Chloramphenicol
An antibiotic produced by Streptomyces venezuelae, an
organism first isolated in 1947 from a soil sample
collected in Venezuela.
Chloramphenicol binds reversibly to the 50S subunit of
the bacterial ribosome and inhibit peptide bond
formation .
 Bacteriostatic broad-spectrum antibiotic that is active
against
aerobic gram +ve & gram - ve organisms
anaerobic gram +ve & gram - ve organisms.
 It is active also against Rickettsiae but not chlamydiae.
 Clinically significant resistance
is due to production of chloramphenicol acetyltransferase,
a plasmid-encoded enzyme that inactivates the drug.

Chloramphenicol Mechanism of Action
 Chloramphenicol inhibits protein synthesis in bacteria
and, less, in eukaryotic cells.
 Chloramphenicol acts primarily by binding reversibly
to the 50S ribosomal subunit.
Although binding of tRNA at the codon recognition
site on the 30 S ribosomal subunit is thus undisturbed,
Chloramphenicol prevent the binding of the amino-
acid-containing end of the aminoacyl tRNA to the
acceptor site on the 50 S ribosomal subunit.
 The interaction between peptidyltransferase and its
amino acid substrate cannot occur, and peptide bond
formation is inhibited .
also can inhibit mitochondrial protein synthesis in
mammalian cells, (mitochondrial ribosomes resemble
bacterial ribosomes)

Susceptibility to microorganisms
Chloramphenicol has a wide range activity that
includes:-
 gram+, gram-, aerobic and anaerobic bacteria such
as :-
Typhoid Fever
Bacterial Meningitis
Anaerobic Infections
Rickettsial Diseases
Brucellosis

Chloramphenicol Pharmacokinetics
Absorption
Chloramphenicol isabsorbed rapidly from the GIT .
peak concentrations of 10 to 13 µg/ml occur within 2
to 3 hours after the administration of a 1-g dose.
 The hydrolysis of chloramphenicol may be due to
esterases of the liver, kidneys, and lungs.
Chloramphenicol itself is rapidly cleared from
plasma by the kidneys.
 This renal clearance of the prodrug may affect the
overall bioavailability of chloramphenicol.

Distribution
Widely distributed in body tissues & fluids &
readily reaches therap. conc. in CSF in the presence
or absence of meningitis .
Drug may accumulate in brain ,
it is also present in bile , milk & placental fluid .

Excretion
The half-life of chloramphenicol has been
correlated with plasma bilirubin concentrations.
 About 50% of chloramphenicol is bound to plasma
proteins.
The half-life of the active drug (4 hours) is not
significantly changed in patients with renal failure .
 The major route of excretion of chloramphenicol is
hepatic metabolism .
 Over a 24-hour period, 75% to 90% of an orally
administered dose is excreted; about 5% to 10% is
in the biologically active form.

Side Effects
The most important adverse effect of
chloramphenicol is on the bone marrow.
Chloramphenicol affects the hematopoietic (Blood
contents) system
aplastic anemia,
fatal pancytopenia .
Leukopenia
 thrombocytopenia

Macrolides
Belong to the Polypetide class of natural products.
bind irreversibly to a site on the 50S subunit of the
bacterial ribosome, inhibiting translocation steps of
protein synthesis ,may also transpeptidation.
 bacteriostatic, may be bactericidal at higher doses
A group of antibiotics consisting of macrolide ring.
It includes :
Erythromycin.
Roxithromycin,
Clarithromycin .
Azithromycin.

Erythromycin
Naturally-occurring macrolide derived from
Streptomyces erythreus.
 Problems with erythromycin
Acid labile
Narrow spectrum.
Poor GI tolerance.
 Short elimination half-life.

Structural derivatives
 Clarithromycin and Azithromycin•
Broader spectrum of activity.
Improved PK (pharmacokinetics)properties –
 Better bioavailability
 Better tissue penetration
 Prolonged half-lives.
 Improved tolerability.

Erythromycin Mechanism of Action
Inhibits protein synthesis by reversibly binding to
the 50S ribosomal subunit .
Suppression of RNA-dependent protein synthesis
by inhibition of translocation of mRNA.
Typically bacteriostatic activity.
Bactericidal at high concentrations against very
susceptible organisms.

Medical use
Erythromycin can be used to treat bacteria
responsible for causing infections of the skin and
upper respiratory tract such as :-
Streptococcus.
 Staphylococcus.
 Haemophilus.
Corynebacterium genera.
The following represents MIC susceptibility data
for a few medically significant bacteria
It may be useful in treating gastro infection.
ntravenous erythromycin may also be used in
endoscopy to help clear stomach contents.

Erythromycin Pharmacokinetics
Absorption
Erythromycin– variable absorption, food may– decrease
the absorption
Clarithromycin– acid stable and well-absorbed–
regardless of presence of food.
Azithromycin –acid stable; food decreases of capsules.
Distribution
 Extensive tissue and cellular distribution.
 clarithromycin and azithromycin with extensive
penetration .
 Minimal CSF penetration

Erythromycin Excretion
Erythromycin is the only macrolide partially
eliminated by the kidney
Hepatically eliminated all
None of the macrolides are removed during
hemodialysis
Variable elimination half –live s
1,4 hours for erythromycin
3 to 7 hours for clarithromycin
68 hours for azithromycin

Erythromycin Side effects
Gastrointestinal – up to 33% caused
Nausea
Vomiting
Diarrhea
Gastric pin
Cholesteric hepatitis –rare
1 to 2 weeks of erythromycin estolate
Dilution of dose slow administration
Other ototoxicity (high dose of erythromycin _
Allergy

3,Antibiotics that inhibit bacterial protein synthesis.ppt

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