WELCOME

OVERVIEW OF AMINOGLYCOSIDES AND

OTHER PROTEIN SYNTHESIS INHIBITORS

Presented By

Maruf Kamal (2008-3-70-006)Sabbir Ahmed (2008-3-70-007)Md. Tanvir Rahman (2009-1-70-018)

Introducton:An aminoglycoside is a molecule or a

portion of a molecule composed of amino-modified sugars.

Several aminoglycosides function as antibiotics that are effective against certain types of bacteria. They include amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin, and apramycin.

History: Aminoglycoside

 Year

 Source organism

streptomycin 1944 Streptomyces griseus

neomycin 1949 Streptomyces fradiae

kanamycin 1957 Streptomyces kanamyceticus

paromomycin 1959 Streptomyces rimosus

spectinomycin 1962 Streptomyces spectabilis

gentamicin 1963 Micromonospora purpurea

tobramycin 1968 Streptomyces tenebrarius

sisomicin 1972 Micromonospora inyoensis

amikacin 1972 semisynthetic derivative of kanamycin

netilmicin 1975 semisynthetic derivative of sisomicin

History:The first aminoglycoside, streptomycin, was isolated

from Streptomyces griseus in 1943. Neomycin, isolated from Streptomyces fradiae, had better activity than streptomycin against aerobic gram-negative bacilli but, because of its formidable toxicity, could not safely be used systemically. Gentamicin, isolated from Micromonospora in 1963, was a breakthrough in the treatment of gram-negative bacillary infections, including those caused by Pseudomonas aeruginosa. Other aminoglycosides were subsequently developed, including amikacin (Amikin), netilmicin (Netromycin) and tobramycin (Nebcin), which are all currently available for systemic use

NomenclatureAminoglycosides that are derived from bacteria of

the Streptomyces genus are named with the suffix -mycin, whereas those that are derived from Micromonospora are named with the suffix -micin.

This nomenclature system is not specific for aminoglycosides. For example, vancomycin is a glycopeptide antibiotic and erythromycin, which is produced from the species Saccharopolyspora erythraea (previously misclassified as Streptomyces) along with its synthetic derivatives clarithromycin and azithromycin, is a macrolide. All differ in their mechanisms of action, however.

Physical and chemical properties:They are water-soluble due to their polar

groups (hydroxyl and amine groups), stable in solution and more active at alkaline than at acid PH.

Aminoglycosides frequently exhibit synergism with β-lactams or vancomycin.

However, aminoglycosides may complex with

β-lactam drugs, resulting in loss of activity and they should not be mixed together for administration.

Specific AgentsAmikacin (Amikin®), Gentamicin (Garamycin®), Kanamycin (Kantrex®), Neomycin, Netilmicin (Netromycin®),Streptomycin, Tobramycin (Nebcin®)

Structure of Aminoglycosides

Mechanism of actionbactericidal; aminoglycosides bind to the

30S subunit of the bacterial ribosome, interfering with the binding of fMet-tRNA and therefore the formation of the initiation complex. Binding to the 30S subunit may also cause misreading of mRNA codons

β-lactams, vancomycin facilitate uptake by Gram-positive organisms

resistance: via plasmid-mediated aminoglycoside-modifying enzymes

Mechanism of action

Pharmacokineticspoor oral absorptionvolume of distribution approximates the

extracellular space (about 0.26 L/kg)(larger in cystic fibrosis patients, about 0.35 L/kg)tissue distribution variable (poor CNS penetration)negligible metabolismrenally eliminated (filtered, with a small amount of

proximal reabsorption)elimination half-life: 2-3 hours (if renal function

normal)

Pharmacodynamicsconcentration-dependent killingpostantibiotic effect (concentration-

dependent)

SARs of AminoglycosidesCrucial for broad

spectrum activityPrimary target for

inactivating enzymes

Congeners with amino groups at 2' and 6' are especially active

SARs of AminoglycosidesMethylation of

these amines does not alter activity,decreases inactivation

Hydroxyls at the 3' or 4‘ position are not critically important

SARs of AminoglycosidesModifications

compromise antibacterial activity

One exception is amikacin with its aminohydroxybutyrate

SARs of AminoglycosidesSubstitution

pattern is somewhat more flexible

Only real requirement is the amine at the 3" position.

Spectrum of activity Aminoglycosides are classified as broad-

spectrum antibiotics, they used for treatment of serious systemic infections caused by

Aerobic Gm –ve bacilli. Aerobic Gm –ve and Gm +ve cocci (with the

exception of Staphylococci) tend to be less sensitive to aminoglycosides and thus the β-lactam and other antibiotics tend to be preferred for the treatment of infections caused by these organisms.

Spectrum of activitybroad gram-negative spectrum including

P. aeruginosagram-positive: synergistic in combination

with ß-lactams, glycopeptidesanaerobes: negligible activityamikacin: Nocardia, MAI, certain rapid-

growing mycobacteria, gentamicin-resistant gram-negative bacilli

streptomycin: multidrug-resistant tuberculosis, tularemia, plague

Adverse reactionsnephrotoxicityproximal acute tubular necrosis (ATN) → ↓ GFRlikely related to inhibition of intracellular

phospholipases in the proximal tubuletends to be reversibleassociated factors: hypotension, dehydration,

duration of therapy, concomitant liver disease, advanced age, other nephrotoxins (vancomycin)

nephrotoxicity correlates with drug accumulation in the renal cortex

Aminoglycoside accumulation in critically ill surgical patients

Toxicity1- Nephrotoxicity 2- Ototoxicity3- Neurotoxicity4- Neuromuscular blockade

Additional adverse reactions with administration of aminoglycosides may include: nausea, vomiting, anorexia, rash, and urticaria.

Toxicityototoxicityvestibulotoxic and cochleotoxicgenerally irreversibledifficult to assesshigh tone frequencies affected firstneuromuscular blockaderare but potentially seriousenhanced by conditions or drugs affecting the NM

junction (e.g., myasthenia gravis, succinylcholine)can be treated with calcium

Contraindications:

Aminoglycosides should not be given to patients requiring long term therapy because of the potential for ototoxicity and nephrotoxicity.

These drugs are contraindicated in patients with: - Preexisting hearing loss - Myasthenia gravis - Parkinsonism - During lactation or pregnancy.

The aminoglycosides are used cautiously in patients with renal failure, in the elderly and in patients with neuromuscular disorders.

Drug interactions: Administration of aminoglycosides with the

cephalosporins may increase the risk of nephrotoxicity.

When the aminoglycosides are administered with loop diuretics there is an increase the risk of ototoxicity (irreversible hearing loss).

There is an increased risk of neuromuscular blockage (paralysis of the respiratory muscles) if the aminoglycosides are given shortly after general anesthetic (neuromuscular junction blockers).

Drug interactions: Increased risk of nephrotoxicity and

ototoxicity when aminoglycosides given with vancomycin.

Increased risk of nephrotoxicity when aminoglycosides given with colistin.

Aminoglycosides antagonize effects of neostigmine.

Streptomycin sulfate

O

CH3

OH O

N-Methyl-L- Glucosamine

Streptomycin

L-Streptose

OH

OH

NH

HO

NH O

H2N

NH

H2N

NH CHO

ONHCH3

OH

HO

HO

Streptidine

Neomycin sulfate

Neosamine C

OCH2NH2

HO

HO NH2 ONH2

NH2

OH

Neomycin C

DeoxystreptamineOO

CH2OH

OHO

O

CH2NH2

HO

HONH2

D-Ribose

13

5

4 13 2

56

5

13

26

54

31

Neosamine C

6

Kanamycin sulfate

O

CH2R1

HO

HO R2 ONH2

NH2

O

1`3`

5`6`

26

5

43

1

HO

O OHHO

HOCH2

H2N

1``

2``4``

5``

Ring I

Ring II

Ring III

Kanamycin A

Kanamycin C

Kanamycin B

R1=NH2, R2=OH

R1=NH2, R2=NH2

R1=OH, R2=NH2

Amikacin

O

CH2NH2

HO

HO OH ONH-C-C-CH2CH2NH2

NH2

O

1`3`

5`6`

26

5

43

1

HO

O OHHO

HOCH2

H2N

1``

2``4``

5``

Ring I

Ring II

Ring III

Amikacin

O OH

H

Gentamicin sulfate

Netilmicin sulfate

26

5

4 1

HO

O OHCH3

OH

NHCH3

1``

2``4``

5``

Ring I

Ring II

Ring III

3``

ONHR

O

NH2

O

CH2OH

H2N 3

6`

5`

4`

3`2`

1`

Sisomicin R= HNetilmicin R= C2H5

Other Protein Synthesis Inhibitors

TetracyclineChloramphenicolMacrolides Mupirocin Quinolones

Mechanisms action of tetracycline

Commercially available tetracyclinesFirst generation (Dose intervals shorter) ChlorotetracyclineOxytetracyclineTetracyclineDmeclocycline• Second Generation (Dose interval longer)Minocycline Methacycline Doxycycline • Third Generation Glycylcycline

Mechanism action of chloramphenicol

Structure of cloramphenicol

MUPIROCIN

Mupirocin is active against many gram-positive and selected gram-negative bacteria. It has good activity against S. pyogenes and methicillin-susceptible and methicillin-resistant strains of S. aureus. It is bactericidal at concentrations achieved with topical application.

Mupirocin inhibits bacterial protein synthesis by reversible inhibition of Ile tRNA synthase. There is no cross-resistance with other antibiotic classes. Clinically insignificant, low-level resistance results from mutations of the gene encoding Ile tRNA synthase or an extra chromosomal copy of a gene encoding a modified Ile tRNA synthase. High-level resistance is mediated by a plasmid or chromosomal copy of a gene encoding a “bypass” synthetase that binds Mupirocin poorly.

Mechanism action of chloramphenicol

Structure of chloramphenicol

Mode of action of Macrolides

Examples of Macrolides

ErythromycinClarithromycin Roxithromycin Azithromycin

Mupirocin is available as a 2% cream or ointment for dermatologic use and as a 2% ointment for intranasal use. The dermatological preparations are indicated for treatment of traumatic skin lesions and impetigo secondarily infected with S. aureus or S. pyogenes. Systemic absorption through intact skin or skin lesions is minimal. Any Mupirocin absorbed is rapidly metabolized to inactive monic acid.

Mupirocin is effective in eradicating S. aureus carriage. The consensus is that patients who may benefit from Mupirocin prophylaxis are those with proven S. aureus nasal colonization plus risk factors for distant infection or a history of skin or soft tissue infections.

Mupirocin may cause irritation and sensitization and contact with the eyes should be avoided.

Systemic reactions to Mupirocin occur rarely, if at all. Application of the ointment to large surface areas should be avoided in patients with renal failure to avoid accumulation of polyethylene glycol from the ointment.

Examples of Quinolones Nalidixic acid Ciprofloxacin Levofloxacin Glatifloxacin Norfloxacin Sparfloxacin Fluroquinolone

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