E. Aminoglycosides

Report
Drugs acting on bacterial protein
biosynthesis
 Proteins are very essential for most of the bacterial
metabolic functions as well as for cell integrity.
 Bacterial cell uses ribosomes to synthesize proteins.
 Targeting protein biosynthesis will produce
bactericidal agents in most of the cases.
 Why targeting the bacterial protein synthesis will be
selective:
 Different diffusion rates between bacterial and
mammalian cells.
 Structural differences between bacterial and
mammalian ribosomes
Aminoglycosides
 They have amino sugar linked together with glycosidic
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bonds.
The first one discovered was streptomycin; obtained
from streptomyces bacteria in 1939.
Most of them are natural products such as kanamycin,
neomycin, gentamicin, netilmicin and tobramycin.
Some are semisynthetics such as amikacin which is
synthesized from kanamycin A.
They are highly polar compounds, because of that they
are not orally bioavailable, either given parenterally ,
topically or for local GIT infections.
Aminoglycosides Chemical
structure
 Most of them have three rings,
some of which are amino sugar
other are simple sugar molecules,
either pentose or hexose.
 Some have four sugar molecules
such as neomycin and paromomycin.
 Generally the pentose do not have
the amino substituents, only the
hexoses have.
Aminoglycosides Chemical
structure
 Highly polar chemical structure.
 Strongly basic compounds…. Form polycationic species
at physiological pH.
 Normally given as sulfate salts to improve their water
solubility.
 Most of them, especially the sulfate salts are highly
water soluble which means:
 Well distributed compounds.
 Do not reach CNS (why?).
 Do not reach bone, fatty or connective tissues (poorly
vascularized tissues).
Aminoglycosides clinical uses
 Parenterally for systemic serious infections caused by gram –
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ve bacilli such as Pseudomonas, acinetobacter and
enterobacter.
Less active on gram +ve and gram –ve cocci.
Not active on anaerobic bacteria (because aminoglycosides
need oxygen dependent transport system to get inside the
cell).
Some are widely used for skin and eye infections for local
antibacterial actions such as neomycin and Gentamicin.
Some are used for GIT infections such as paromomycin and
tobramycin.
Have good activity against Ps. aeruginosa especially in
combination with penicillins.
Combination of aminoglycosides
and penicillins
 Mainly used for Ps. Aeruginosa infections.
 The commonly used combinations:
 Carbenicillin + Gentamicin.
 Penicillin G + streptomycin for Enterococci infections
(endocarditis).
 Here penicillins will destroy the integrity of the cell
wall that will help the aminoglycosides to reach
ribosomes and inhibit protein biosynthesis.
Mechanism of action
 Aminoglycosides directly inhibit protein synthesis by
interfering with the translation process, this done by
direct binding to the ribosomal 30S subunit.
 Inhibit the initiation process.
 Can cause misreading of the codons which may results
in protein mutation (mainly the deoxystreptamine
containing aminoglycosides).
 All aminoglycosides are bacteriostatic (at lower
dose)and bactericidal at higher dose.
 Spectinomycin is a bacteriostatic even at
higher dose.
Bacteria protein synthesis
Bacteria protein synthesis
 Bacterial protein synthesis can be divided into four phases:
 Initiation: where a functionally competent ribosome is assembled in
the correct place on an mRNA ready to commence protein synthesis.
 Elongation: whereby the correct amino acid is brought to the
ribosome, is joined to the nascent polypeptide chain, and the entire
assembly moves one position along the mRNA.
 Termination: which happens when a stop codon is reached, there is no
amino acid to be incorporated and the newly-synthesized polypeptide
is released from the ribosome.
 Disassembly: whereby a special factor binds to the ribosome so that it
can release the mRNA and tRNA that is still bound to it and so that it
can be recycled in another round of protein synthesis.
Mechanism of bacterial resistance
 Bacteria has two major resistant mechanisms to
aminoglycosides:
1.
2.
Affecting aminoglycosides uptake by the cell: mainly
adapted by Ps. aeruginosa by making some sort of
mutation in the energy dependant transport system
required to get such compounds inside the cell.
Inactivating aminoglycosides by changing the
chemical structure, especially the essential functional
groups for activity.
Inactivating enzymes
 Nine different types of aminoacetyl transferase (AAC):
responsible for acetylating the amino groups in the
structure from ring I and II.
 Aminoglycoside Phosphotransferase (APH):
phosphorylate the hydroxyl groups from ring I and III.
APH
Ring I
Ring III
AAC
APH
Kanamycin A
Ring II
AAC
Inactivating enzymes
 New derivatives have been made to overcome the
enzymatic inactivation by these enzymes.
 Removal of the functional group susceptible to
attacking by the inactivating enzymes can lead to
more active agents against the resistant strains
 Gentamicin and tobramycin lack the 3΄ OH in ring I
which make them resistant to APH.
 Amikacin has the 3-NH2 being acylated (by Lhydroxyaminobuteroyl amide (L-HABA)), that makes it
more resistant to AAC at this site.
No OH group
Gentamicin
Amikacin
No OH group
Tobramycin
SAR of aminoglycosides
4΄΄
Ring III
6΄΄
5΄΄
3΄΄ 2΄΄
2΄
1΄
1΄΄
6
4
5
1
2
4΄
3΄
Ring I
5΄
6΄
3
Ring II
 Ring I is important for broad spectrum in activity, at
the same time it is the major site for enzymatic
inactivation by AAC and APH.
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Amino group at 6΄ and 2΄ are important.
Phosphorylation of 3΄ OH will reduce the binding to
ribosomes 30S subunit.
SAR of aminoglycosides
4΄΄
Ring III
6΄΄
5΄΄
3΄΄ 2΄΄
2΄
1΄
1΄΄
6
4
5
1
2
4΄
3΄
Ring I
5΄
6΄
3
Ring II
 Ring II can accept few structural modifications and
retaining the same activity: example is the acetylation of
the amino group at position-1 (amikacin).
 Ring II can be ribose, streptose (five memeberd ring) or
streptamine (six memeberd ring).
 Ring III less sensitive to structural changes but the amino
group at position 3΄΄ can be 1° or 2° for maximum activity.
Streptomycin
 Active against Gram –ve more than Gram +ve
bacteria, especially on mycobacterium bacteria.
 Bacteria rapidly developed resistance to streptomycin,
because of that it is not recommended as
monotherapy and should be given in combination.
 Can not be given orally (why?).
 Will not be absorbed.
 Could be destroyed in GIT acidity.
 At lower dose it only induce misreading of the mRNA.
Paromomycin
 It has four sugar rings in its structure.
 Has a broad spectrum of action.
 Has poor oral availability.
 Mainly used for GIT infections caused by salmonella,
and shigella or that caused by protozoa specially in
amaebiasis.
Gentamicin
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Isolated from the gram +ve bacteria; Micromonospora.
Mainly active on Gram –ve bacteria.
Has high activity against Ps. aeruginosa.
Mainly used topically for eye, ear and skin infections
due to :
 Poor oral bioavailability (why?).
 Serious systemic toxicity (otto toxicity and
nephrotoxicity).
 Given IV injections for serious systemic infections
caused by Ps. aeruginosa
Spectinomycin
 It is aminocyclitol antibiotic.
 The structure contains the unstable hemiacetal, so it
should be freshly prepared and used directly.
 Is a bacteriostatic agents, mainly act on the translation
process.
 It has poor oral absorption, it should be given
parenterally mainly as deep IM injections.
 Used in gonorrhea.
Other agents acting on bacterial
protein synthesis

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