This article consists of 29 pages and 5483 words. In order to have full access to this article, email us at thedocumentco@hotmail.co.uk

Ref No: 3657

History of Aminoglycosides

Aminoglycosides are one of the bactericidal drugs which are used for action against gram-negative bacteria and gram-positive bacteria. There are multiple drugs subtypes in aminoglycosides. These include streptomycin, neomycin, kanamycin, paromomycin, spectinomycin, gentamicin, tobramycin, sisomicin, amikacin, and netilmicin.

They occur naturally as well as in the form of synthetic and semi-synthetic compounds. The term aminoglycoside was given in accordance with the structure of aminoglycosides. They consist of the amino group attached to some of the glycosides giving their name as aminoglycosides (Hofer, 2013). These are the group of drugs that are produced from the naturally occurring organisms belonging to the Actinomycetes family.

These are the antimicrobial agents that were first discovered in 1944 from the organism, known as Streptomyces griseus, which is a mold-like bacterium. It was discovered by American biochemists Selman Waksman, Albert Schatz, and Elizabeth Bugie via bacteria that were found in the soil (Wilson, 2007).

 

The first drug of the series was streptomycin that proved its efficacy in the treatment of tuberculosis, which was previously a life-threatening condition. In this series, the addition of new members continued to contribute. These agents included kanamycin, gentamicin, and tobramycin. In the era of 1970s certain other agents, like dibekacin, amikacin, and netilmicin, were further introduced; these were semi-synthetic aminoglycosides.

Since then there has been a decline in the research process of streptomycin use. However, it has been found that these drugs have shown different working that encouraged the scientists to study about them and led to their introduction (Avent et al, 2011).

Gentamicin is considered as the workhorse of the aminoglycosides family. They were introduced in the early 1960s and are effective against gram-negative infections (Avent et al., 2011).  It was isolated from Micromonospora purpurea that is a gram-positive bacteria. This bacteria is found in soil and water (Balakumar, Rohilla & Thangathirupathi, 2010).

The other aminoglycosides which were introduced comprised of neomycin, introduced in 1949; tobramycin, introduced in 1963; tobramycin, introduced in 1967, and anisomycin, introduced in 1970. All of these drugs showed great potential to halt the activity of gram-negative, and some of the gram-positive bacteria, with the inclusion of Pseudomonas species (Becker & Cooper, 2013).

 

As the newly effective drugs, the use of aminoglycosides became common, where they were started to be used in a wide variety of patients with multiple illnesses. This widespread use led to the development of resistance against aminoglycosides. New semi-synthetic drugs were introduced because the previous aminoglycosides were getting resistant to the bacteria and had a higher level of toxicities than the newly introduced drugs.

The newly semi-synthetic drugs had a better pharmacological profile than the previous aminoglycosides and were named as the second generation of aminoglycosides. These included the following: Dibekacin that was introduced in 1971; Amikacin was in traduced in 1972; Arbekacin was isolated in 1973; Isepamicin was discovered in 1975, and Netilmicin that was discovered in 1976. It was also found that the newly developed semi-synthetic aminoglycosides, especially Amikacin, were less susceptible to the target of Aminoglycoside-modifying enzymes (Becker & Cooper, 2013).

 

The advent of aminoglycosides had continued for a very long time, while they have continued to evolve. For example, Gentamicin was given in multiple doses in a day, but with the introduction of long-acting gentamicin in the 1990s, this dose has been decreased to once daily dosing. This once-daily dosing is effective than multiple dosing and is less damaging to the kidneys. This once-daily dosing has caused achievement of maximum concentration, decline in the minimum inhibitory concentration (MIC) ratio, decline in the area under the curve (AUC), decreased post-antibiotic effect and decline in the cost of the doses (Avent et al., 2011). With

the introduction of more powerful and other broad-spectrum antibiotics like fluoroquinolones, carbapenems, cephalosporin, and β-lactam/ β-lactamase inhibitor combinations, it has caused a decline in the development and research of new aminoglycosides. Isepamicin was discovered in 1988 and Arbekacin was found in 1990. Since the advent of these two antibiotics, no new antibiotics in the family of aminoglycosides were discovered. It was found in 2010 that the contribution of aminoglycosides in 2010 was limited to only 2.7% in the market.

This decline in their use does not mean that they have completely vanished from the clinical side. They are still in use in many of the nosocomial infections which are resistant to other antibiotics. They also have their important contribution in the infection caused by gram-negative infections (Becker & Cooper, 2013).

 

The main culprit in the development of resistance of these aminoglycosides was related to enzymatic breakdown by the bacteria. Aminoglycoside-modifying enzymes are associated with changes in the −OH or −NH₂ groups on the 2-deoxystreptamine nucleus or the sugar moieties. These modifying enzymes can be nucleotidyltransferases, phosphotransferases, or acetyltransferases.

 

Mechanism of Action of Aminoglycosides

The mechanism of action of aminoglycosides allows it to attack the oxygen-dependent (aerobic), gram-negative bacteria cells as these possess the mechanism and setting that allow the aminoglycosides to act on the bacterial growth. They work more good in alkaline pH, which increases their absorption (Becker & Cooper, 2013).

The mechanism of action of aminoglycosides was identified in 1980, where it was found that they target the 16S r RNA subunit of the 30S bacterial ribosome. Since then, there has been extensive research to identify the various methods with which aminoglycosides attack the bacteria (Houghton et al., 2010).

The general mechanism of action of aminoglycosides resides in its ability to displace adenine from the three unpaired adenine residues in the decoding loops. This causes their orientation into a flipped-out position, which is usually seen in mRNA decoding. This sort of activity causes a reduction in the normal translation process of the protein synthesis as the mRNA–tRNA complexes are abnormal. This results in the development of nonfunctional protein synthesis in the bacterial cells leading to their death. This activity is seen in tobramycin, geneticin, amikacin, and paromomycin (Houghton et al., 2010).

Paromomycin also can interfere with the normal activity of the 70S in the translocation process in order to prevent the anti-activation activity of translation initiation factor 3 (IF-3). This translation initiation factor is associated with the inhibition of the dissemination of ribosomal assemble after translation. This leads to strong bonding of the 50S and 30S subunits resulting in the stabilization of 70S complexes. This further causes defects in the inner mobility and translocation of the tRNAs. This activity may be due to the ability of interact with aminoglycosides with 16S RNA.

This activity of aminoglycosides against RNA is associated with the interaction of an amino acid group of aminoglycosides, which are positively charged, and a phosphate group of RNA, which are negatively charged. The other source of interaction occurs because of the hydrogen bonding among different hydroxyl and amino groups of aminoglycosides and RNA. All of these interactions result in a strong bond between RNA and aminoglycosides which results in a decline in the translation activity of bacterial RNA (Houghton et al., 2010).

 

It has been found that there is two mechanisms with which the ability of aminoglycosides is enhanced to bind with its target. One of the very significant interaction comes from the electrostatic bond between the positively charged amino group of aminoglycoside and the negatively charged phosphate of RNA. The other contributor in this electrostatic interaction is the hydrogen bonding between many of the bonds of the RNA and aminoglycosides.

All of these bindings create very tight interactions of aminoglycosides with their targets. For example, the ring II of paromomycin can bind with the U1406, U1495, and G1494 of the 16S RNA of bacteria via hydrogen bonding. On the other hand ring, I can bind with the A1408, A1493, A1492, and G1491 of the RNA of the bacteria depending on the substitution. These are the rings, which are most common among aminoglycosides. Ring II does not show significant interaction.

The additional attachment of substitutes on the 5 or 6 position of the pseudostreptamine ring shows more effect on the specificity of the aminoglycosides. The rings of kanamycin A, neamine, gentamicin C1A, ribostamycin, lividomycin, neomycin B, and tobramycin having oligonucleotides with the RNA A decoding site has importance not only in recognition but also in the interaction. An important implication in the working of aminoglycosides is that it does not attack the ribosomes of the humans. This selectivity of aminoglycosides is attributed to the difference in the nucleotide sequence difference between that of bacteria and human beings (Houghton et al., 2010).

 

One of the important aspects of the action of aminoglycosides depends on the permeability of the bacterial cells. This affects the selectivity of aminoglycosides. As discussed before, aminoglycosides are polycationic. This polycationic nature prevents their ability to sweep in many of the eukaryotic cells. On the other hand, this polycationic nature……