Amikacin Amikin

Ball-and-Stick Model

NH OH

= Hydrogen

Space-filling Model

= Carbon

= Hydrogen

= Oxygen

Nitrogen

Year of discovery: 1972; Year of introduction: 1981 (Bristol-Myers Squibb); Drug category: Aminoglycoside (amino-sugar) antibiotic; Main uses: For the treatment of serious infections by aerobic Gram-negative bacilli that are resistant to other aminoglycosides; Related drugs: Gentamicin (Genoptic), Kanamycin (Kantrex).

Aminoglycosides are naturally occurring bactericidal organic molecules in which one or two amino-sugar units (blue) are linked to a central sugar nucleus (red). The first member of the class, streptomycin, was discovered in 1943 by S.A. Waksman and A. Schatz who isolated this compound from the soil microbe Streptomyces griseus. Streptomycin effectively attacks aerobic Gram-negative bacteria that are not sensitive to the penicillins. Within a few years, millions of tuberculosis patients had been successfully treated with streptomycin. As a result, the death rate from tuberculosis plummeted. Waksman was awarded the Nobel Prize in Medicine in 1952.

HN NH, HO,, .X. ,,OH NH j h,nan'S^noh OHC-4—v, V—<

Streptomycin

/yvV

Tobramycin (Tobi )

Unfortunately, streptomycin-resistant bacterial strains appeared soon after its introduction. However, a number of novel and more potent aminoglycosides were subsequently discovered as a result of intensive research. Among these aminoglycosides were gentami-cin C, kanamycin A, tobramycin, netilmicin and amikacin. Intravenous gentamicin is now mostly used for the treatment of urinary tract infections and pneumonia. Inhaled tobramycin (Tobi™) is effective in treating people with cystic fibrosis, a chronic respiratory disease in which there is a high risk of infection. Amikacin, a semisynthetic derivative of kanamycin A, was designed to be resistant to the enzymes acetylase, adenylase and Phosphorylase that catalyze the inactivation of all previously known aminoglycosides. Amikacin is prepared by attaching the y-amino-a-hydroxybutyryl group (L-haba group, shown in green above) to kanamycin A.1 Patients receiving amikacin should be monitored to detect hearing loss or kidney damage.

The mechanism of action of aminoglycosides has not been fully elucidated. However, their primary target is the bacterial small ribosomal unit (30S), the site of protein synthesis. Amikacin binds to the A-site in the 16S rRNA and interferes with the initiation of protein synthesis. This leads either to the accumulation of abnormal initiation complexes or to the misreading of the mRNA template. The latter leads to the incorporation of incorrect amino acids and the formation of proteins that are toxic to the microorganism. The X-ray picture A (below) shows two amikacin molecules (red) bound to the A-site/ The close-up view B shows the L-haba group specifically interacting with two G:C base pairs.

1. Anti-lnfec. Agents in Med. Chem. 2006, 5, 255-271; 2. Biochimie 2006, 88, 1027-1031 (2G5Q); Refs. p. 175

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