G. F. Busscher, F. Rutjes, F. V. van Delft
Feb 10, 2005
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Influential Citations
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Abstract
A key structural feature of the aminoglycoside antibiotics is a 1,3-diaminocyclohexanetriol termed streptamine or, in cases where the 2-hydroxy function is deoxygenated as in most aminoglycosides, 2-deoxystreptamine. This central position of 2-deoxystreptamine suggests a crucial role for the biological activity of the aminoglycosides, that form a large class of clinically important antibiotics with a broad antibacterial spectrum and proven efficacy, particularly against Gram-negative bacteria (Table 1).1 Most of the aminoglycosides are naturally occurring substances and are readily obtained from actinomycetes of either genus Streptomyces (labeled “-mycin”) or Micromonospora (labeled “-micin”).2 The most relevant members of the family are streptomycin, tobramycin, and gentamicin, the latter of which is used in the clinic most frequently due to its low cost and reliable activity. In general, aminoglycosides show a strong synergistic effect upon coadministration with penicillin, a particularly useful combination for treatment of patients with infections of unknown origin. Some semisynthetic derivatives, that is, amikacin, netilmicin, arbekacin, isepamicin, and dibekacin, are also on the market and display particular activity against bacterial strains that have developed resistance against the early aminoglycosides.3 However, in recent years it has become apparent, after a long era of marginal interest in the research and development of antibacterials, that the battle against pathogenic bacteria is not over. In contrast, resistant strains of bacteria are reported with increasing frequency, with the associated dramatic consequences such as untreatable patients or the temporary closure of hospital intensive cares.4 Apart from being versatile antibiotics, recent years have seen a shift of scientific interest in aminoglycosides to a related field of interest that has the potential of much broader application: the regulation of protein production at the RNA-level. Due to the fact that aminoglycosides are rather promiscuous ligands for all sorts of RNA, often in low micromolar concentration, they have earned themselves a strong position in the emerging research field “RNA as a drug target”: the perception that RNA plays a central (and active) role in the biochemical pathway required to produce proteins from DNA provides nearly un* To whom correspondence should be addressed. Telephone: +31(0)24.3652373. Fax: 31(0)24.3653393. E-mail: F.vandelft@ science.ru.nl. † In memory of the late Professor Jacques H. van Boom. Volume 105, Number 3