Aminoglycosides and Aminoglycoside Resistance 2.1

Aminoglycoside Antibiotics

The first aminoglycoside, streptomycin, was isolated from the soil bacterium Streptomyces griseus in 1944 (Schatz et al. 1944). Streptomycin proved to be the first successful drug against Mycobacterium tuberculosis and became widely popular in the 1940s and 1950s. The impact of streptomycin was of such significance that Selman A. Waksman was awarded the Nobel Prize in Medicine in 1952 for its discovery. While streptomycin continues to be an integral part of modern chemotherapy for tuberculosis since its clinical introduction over 50 years ago, a variety of natural and semisynthetic aminoglycosides with broad antimicrobial spectra have also been discovered and developed. Despite their toxic effects on the kidney and the inner ear (Forge and Schacht 2000), aminoglycosides are among the most commonly used antibiotics due to their low cost and high efficacy against both grampositive and gram-negative bacteria, and in some cases, protozoal infections (Berman and Fleckenstein 1991).

From a chemical perspective, aminoglycosides are a group of structurally diverse, water soluble, polycationic molecules. They contain an aminocycli-tol nucleus and two or three aminosugar rings linked to the nucleus via gly-cosidic bonds. They can be grouped into two main categories based on the structure of the central aminocyclitol ring. The first group, which includes streptomycin, contains a streptidine derivative; the second, larger group, which includes neomycin and kanamycin, contains a 2-deoxystreptamine ring derivatized at either the 4- and 5-positions or the 4- and 6-positions (Fig. 1). Conventionally, the numbering of the 6-aminohexose ring linked to the 4-position of the 2-deoxystreptamine is designated by prime ('), and the pentose or hexose ring linked to the 5- or 6-position is denoted by double prime (").

Unlike many other antibiotics, aminoglycosides are bactericidal compounds. The primary target of these drugs in the bacterial cell is the 30S ri-bosomal RNA, as shown by chemical footprinting experiments (Moazed and Noller 1987), and more recently, evidence from crystallographic studies (Carter et al. 2000). Nonetheless, some details concerning the uptake and action of aminoglycosides remain elusive. Existing evidence indicates that the first step of aminoglycoside uptake involves an energy-requiring transport across the cell membrane (Wright et al. 1998). Once inside the cell, the aminoglycosides bind to the A-site (the decoding site) of the 16S ribosomal RNA (Moazed and Noller 1987) and trigger certain conformational changes in the A-site that normally occur only when there is a correct interaction between cognate tRNA and mRNA (Pape et al. 2000; Ogle et al. 2002; Rodnina et al. 2002). As a result, the stability of the binding of near-cognate aminoac-yl-tRNA to this site is increased and the ribosome is unable to discriminate between cognate and near- or non-cognate tRNA-mRNA complexes, and the production of defective proteins ensues. Subsequently, the faulty proteins are presumably inserted into the cytoplasmic membrane, leading to the loss of membrane integrity. Additional aminoglycosides are then rapidly transported across the damaged membrane, leading to the accumulation of the drug in the cytoplasm, saturation of all ribosomes and ultimately cell death (Wright et al. 1998).

Neomycin B (4,5-disubstituted 2-deoxystreptamine)

Kanamycin A (4,6-disubstituted 2-deoxystreptamine)

Fig. 1 Examples of two aminoglycoside antibiotics based on 2-deoxystreptamine. Neomycin B is derivatized at the 4- and 5-positions of the central 2-deoxystreptamine ring, while kanamycin A is derivatized a the 4- and 6-positions

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