An aminoglycoside is a molecule or a portion of a molecule composed of amino-modified
sugars

Glycoside

In chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...

.

Several aminoglycosides function as antibiotics that are effective against certain types of bacteria. They include amikacin

Amikacin

Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.-Administration:Amikacin may be...

, arbekacin

Arbekacin

Arbekacin is a semisynthetic aminoglycoside antibiotic. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus . Arbekacin was originally synthesized from dibekacin in 1973. It has been registered and marketed...

, gentamicin

Gentamicin

Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...

, kanamycin

Kanamycin

Kanamycin sulfate is an aminoglycoside antibiotic, available in oral, intravenous, and intramuscular forms, and used to treat a wide variety of infections. Kanamycin is isolated from Streptomyces kanamyceticus.-Mechanism:...

, neomycin

Neomycin

Neomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951...

, netilmicin

Netilmicin

Netilmicin is a member of the aminoglycoside family of antibiotics. These antibiotics have the ability to kill a wide variety of bacteria. Netilmicin is not absorbed from the gut and is therefore only given by injection or infusion...

, paromomycin, rhodostreptomycin, streptomycin

Streptomycin

Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

, tobramycin, and apramycin

Apramycin

Apramycin is an aminoglycoside antibiotic used in veterinary medicine. It is produced by Streptomyces tenebrarius.-Mechanism of action:...

 .

Nomenclature

Aminoglycosides that are derived from bacteria of the Streptomyces

Streptomyces

Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...

genus

Genus

In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...

 are named with the suffix -mycin, whereas those that are derived from Micromonospora

Micromonospora

Micromonospora is a genus of bacteria of the family Micromonosporaceae. They are gram-positive, spore-forming, generally aerobic, and form a branched mycelium; they occur as saprotrophic forms in soil and water...

are named with the suffix -micin.

This nomenclature system of Heidi and Pam is not specific for aminoglycosides. For example, vancomycin

Vancomycin

Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...

 is a glycopeptide antibiotic

Glycopeptide antibiotic

Glycopeptide antibiotics are a class of antibiotic drugs. The class is composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin....

 and erythromycin

Erythromycin

Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...

, which is produced from the species Saccharopolyspora erythraea

Saccharopolyspora erythraea

Saccharopolyspora erythraea, formerly known as Streptomyces erythraeus, is a species of actinomycete bacteria within the genus Saccharopolyspora.Saccharopolyspora erythraea is known for the production of the macrolide antibiotic erythromycin...

(previously misclassified as Streptomyces

Streptomyces

Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...

) along with its synthetic derivatives clarithromycin

Clarithromycin

Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...

 and azithromycin

Azithromycin

Azithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics...

, is a macrolide

Macrolide

The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...

. All differ in their mechanisms of action, however.

Mechanisms of action

Aminoglycosides have several potential antibiotic mechanisms, some as protein synthesis inhibitor

Protein synthesis inhibitor

A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins....

s, although their exact mechanism of action is not fully known:

• They interfere with the proofreading
  Proofreading (biology)
  The term proofreading is used in genetics to refer to the error-correcting processes, first proposed by John Hopfield and Jacques Ninio, involved in DNA replication, immune system specificity, enzyme-substrate recognition among many other processes that require enhanced specificity...
  
   process, causing increased rate of error in synthesis with premature termination.
• Also, there is evidence of inhibition of ribosomal translocation
  Ribosomal translocation
  Ribosomal translocation is a step in both:*Eukaryotic elongation and*Prokaryotic elongation, during translation of messenger RNA into proteins...
  
   where the peptidyl-tRNA moves from the A-site to the P-site.
• They can also disrupt the integrity of bacterial cell membrane.

They bind to the bacterial 30S

30S

30S is the smaller subunit of the 70S ribosome of prokaryotes. It is a complex of ribosomal RNA and ribonucleoproteins that functions in mRNA translation...

 ribosomal

Ribosome

A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

 subunit (some work by binding to the 50S

50S

50S is the larger subunit of the 70S ribosome of prokaryotes. It is the site of inhibition for antibiotics such as macrolides, chloramphenicol, clindamycin, and the pleuromutilins. It includes the subunits 5S and 23S.-Structure:...

 subunit)

There is a significant variability in the relationship between the dose administered and the resultant plasma level in blood. Therapeutic drug monitoring

Therapeutic drug monitoring

- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...

 (TDM) is necessary to obtain the correct dose. These agents exhibit a post-antibiotic effect in which there is no or very little drug level detectable in blood, but there still seems to be inhibition of bacterial re-growth. This is due to strong, irreversible binding to the ribosome, and remains intracellular long after plasma levels drop. This allows a prolonged dosage interval. Depending on their concentration, they act as bacteriostatic

Bacteriostatic agent

A bacteriostatic agent or bacteriostat, abbreviated Bstatic, is a biological or chemical agent that stops bacteria from reproducing, while not necessarily harming them otherwise. Depending on their application, bacteriostatic antibiotics, disinfectants, antiseptics and preservatives can be...

 or bactericidal agents.

The protein synthesis inhibition of aminoglycosides does not usually produce a bactericidal effect, let alone a rapid one as is frequently observed on susceptible Gram-negative bacilli. Aminoglycosides competitively displace cell biofilm-associated Mg²⁺ and Ca²⁺ that link the polysaccharides of adjacent lipopolysaccharide molecules. "The result is shedding of cell membrane blebs, with formation of transient holes in the cell wall and disruption of the normal permeability of the cell wall. This action alone may be sufficient to kill most susceptible Gram-negative bacteria before the aminoglycoside has a chance to reach the 30S ribosome."

The antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane, it is presumed, accounts for most of the bactericidal activity. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes.

Aminoglycosides are useful primarily in infections involving aerobic

Aerobic organism

An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...

, gram-negative

Gram-negative

Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 bacteria, such as Pseudomonas

Pseudomonas

Pseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...

, Acinetobacter

Acinetobacter

Acinetobacter [asz−in−ée−toe–back−ter] is a genus of Gram-negative bacteria belonging to the Gammaproteobacteria. Acinetobacter species are non-motile and oxidase-negative, and occur in pairs under magnification....

, and Enterobacter

Enterobacter

Enterobacter is a genus of common Gram-negative, facultatively-anaerobic, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of the these bacteria are pathogenic and cause opportunistic infections in immunocompromised hosts and in those who are on mechanical ventilation...

. In addition, some Mycobacteria, including the bacteria that cause tuberculosis

Tuberculosis

Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, are susceptible to aminoglycosides. The most frequent use of aminoglycosides is empiric therapy for serious infections such as septicemia, complicated intraabdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibiotics.

Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple-drug-resistant strains.

Infections caused by gram-positive

Gram-positive

Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past, the aminoglycosides have been used in conjunction with beta-lactam antibiotics in streptococcal infections for their synergistic effects, in particular in endocarditis

Endocarditis

Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...

. One of the most frequent combinations is ampicillin (a beta-lactam, or penicillin-related antibiotic) and gentamicin. Often, hospital staff refer to this combination as "amp and gent" or more recently called "pen and gent" for penicillin and gentamicin.

Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi, and viruses.

Nonsense suppression

The interference with DNA proofreading has been exploited to treat genetic diseases that result from premature stop codes (leading to early termination of protein synthesis and truncated proteins). Aminoglycosides can cause the cell to overcome the stop code, insert a random amino acid, and express a full-length protein.

The aminoglycoside gentamicin

Gentamicin

Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...

 has been used to treat cystic fibrosis

Cystic fibrosis

Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...

 (CF) cells in the laboratory to induce them to grow full-length proteins. CF is caused by a mutation in the gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 coding for the cystic fibrosis transmembrane conductance regulator

Cystic fibrosis transmembrane conductance regulator

Cystic fibrosis transmembrane conductance regulator is a protein that in humans is encoded by the CFTR gene.CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes...

(CFTR) protein. In approximately 10% of CF cases, the mutation in this gene causes its early termination during translation, leading to the formation of is truncated and non-functional CFTR protein. It is believed that gentamicin

Gentamicin

Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...

 distorts the structure of the ribosome-RNA complex, leading to a mis-reading of the termination codon

Stop codon

In the genetic code, a stop codon is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide...

, causing the ribosome

Ribosome

A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

 to "skip" over the stop sequence and to continue with the normal elongation and production of the CFTR protein.

Routes of administration

Since they are not absorbed from the gut, they are administered intravenously and intramuscularly. Some are used in topical preparations for wounds. Oral administration can be used for gut decontamination (e.g., in hepatic encephalopathy). Tobramycin may be administered in a nebulized form.

Clinical use

The recent emergence of infections due to Gram-negative bacterial strains with advanced patterns of antimicrobial resistance has prompted physicians to reevaluate the use of these antibacterial agents. This revived interest in the use of aminoglycosides has brought back to light the debate on the two major issues related to these compounds, namely the spectrum of antimicrobial susceptibility and toxicity. Current evidence shows that aminoglycosides do retain activity against the majority of Gram-negative clinical bacterial isolates in many parts of the world. Still, the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment makes physicians reluctant to use these compounds in everyday practice. Recent advances in the understanding of the effect of various dosage schedules of aminoglycosides on toxicity have provided a partial solution to this problem, although more research still needs to be done in order to overcome this problem entirely.

Aminoglycosides are in pregnancy category D, that is, there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

External links

• MedlinePlus drug information - Aminoglycosides (Systemic)
• Science Daily Bacterial 'Battle for Survival' - Rhodostreptomycin