Aminoglycoside modifying enzymes
Section snippets
General aspects
Aminoglycoside antibiotics are a complex family of compounds characterized for having an aminocyclitol nucleus (streptamine, 2-deoxystreptamine, or streptidine) linked to amino sugars through glycosidic bonds. In addition, other compounds such as spectinomycin, which is an aminocyclitol not linked to amino sugars, or compounds that include the aminocyclitol fortamine are also included in this family (Bryskier, 2005, Veyssier and Bryskier, 2005). Aminoglycosides are primarily used in the
Mechanisms of resistance
Aminoglycoside resistance occurs through several mechanisms that can coexist simultaneously in the same cell (Alekshun and Levy, 2007, Houghton et al., 2010, Magnet and Blanchard, 2005, Taber et al., 1987, Tolmasky, 2007a). Described mechanisms include modification of the target by mutation of the 16S rRNA or ribosomal proteins (Galimand et al., 2005, O’Connor et al., 1991); methylation of 16S rRNA, a mechanism found in most aminoglycoside-producing organisms and in clinical strains (Doi and
Aminoglycoside modifying enzymes
Aminoglycoside modifying enzymes catalyze the modification at –OH or –NH2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be acetyltransferases (AACs), nucleotidyltranferases (ANTs), or phosphotransferases (APHs) (Fig. 1). The combination of mutagenesis, which leads to continuous generation of new enzyme variants that can utilize an ever growing number of antibiotics as substrates, with the coding genes’ ability to transfer at the molecular level as part of integrons,
Strategies to overcome the effect of aminoglycoside modifying enzymes
The development of new aminoglycosides, which is being pursued using numerous different approaches, is an obvious path to overcome the action of aminoglycoside modifying enzymes. Strategies and perspectives for the generation of novel aminoglycosides or aminoglycoside derivatives such as dimers or conjugates to small molecules have been recently reviewed (see Green et al., 2010, Houghton et al., 2010, Tolmasky, 2007a, Welch et al., 2005). ACHN-490, a novel aminoglycoside named neoglycoside
Concluding remarks
Inactivation by enzymatic modification is the most prevalent mechanism of resistance to aminoglycoside antibiotics in the clinical setting. The raise and dissemination of aminoglycoside modifying enzymes has reduced the efficacy of these antibiotics and in some cases rendered them virtually unusable. There are three kinds of aminoglycoside modifying enzymes, nucleotidyltranferases, phosphotransferases, or acetyltransferases, which catalyze the modification at different –OH or –NH2 groups in the
Acknowledgements
The authors’ work cited in this review article was funded by Public Health Service grant 2R15AI047115 (to M.E.T.) from the National Institutes of Health. M.S.R. is a research career member of C.O.N.I.C.E.T.
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