New plasmid-mediated resistances to antimicrobial agents
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MI NI-R EVIE W
New plasmid-mediated resistances to antimicrobial agents Patrice Courvalin
Received: 14 November 2007 / Revised: 14 November 2007 / Accepted: 17 November 2007 / Published online: 20 December 2007 © Springer-Verlag 2007
Recently, additional plasmid-borne mechanisms of resistance to aminoglycosides and quinolones have been reported in human clinical isolates. Methylation of ribosomal RNA, a self-defence mechanism in the aminoglycoside producing microorganisms, has been found to confer high level to all aminoglycosides used to treat systemic infections. Low-level resistance to the synthetic Xuoroquinolones was shown to be due to target protection, detoxiWcation by a mutant aminoglycoside modifying enzyme, and eZux. Recent years have witnessed the emergence and spread of new plasmid-borne mechanisms of antibiotic resistance, in particular to two drug classes: the aminoglycosides and the Xuoroquinolones. Despite the development of new -lactams and Xuoroquinolones, aminoglycosides are still extensively used for the treatment of severe infections due to Gram-negative bacteria. They cause translational errors and inhibit translocation by binding to a highly conserved motif of 16S rRNA. Since their introduction into clinical use, four mechanisms of resistance to these drugs have been reported in bacterial human pathogens: (1) decreased intracellular accumulation of the antibiotic by alteration of outer membrane permeability (Hancock 1981), diminished inner membrane transport (Taber et al. 1987), or active eZux (Magnet et al. 2001; Moore et al. 1999), (2) enzymatic modiWcation of the drug which is the most common (Shaw et al. 1993), (3) modiWcation of the target by mutation in ribosomal proteins or in 16S rRNA (O’Connor et al. 1991),
Communicated by Ercko Stackebrandt. P. Courvalin (&) Unité des Agents Antibactériens, Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15, France e-mail: [email protected]
(4) trapping of the drug (Magnet et al. 2003; Ménard et al. 1993). Most recently, a Wfth mechanism, post-transcriptional methylation of ribosomal RNA using S-adenosylmethionine as a co-factor, has been reported which confers high-level resistance to all available aminoglycosides used for systemic therapy, except streptomycin (for a review see Doi and Arakawa 2007). The Wrst gene for this type of resistance, armA (Galimand et al. 2003), was shown to be part of a composite transposon (Galimand et al. 2005) carried by a conjugative plasmid in a clinical isolate of Klebsiella pneumoniae, and to encode an enzyme that methylates the N7 position of nucleotide G1405 in 16S rRNA (Liou et al. 2006). Reports followed of four methyltransferases, RmtA, B, C, and D that are only 29–31% identical with armA (for a review see Doi and Arakawa 2007). Post-transcriptional methylation of ribosomal RNA is particularly eYcient since it modiWes all 16S rRNA copies, in contrast with rDNA mutations which have to occur in a minimum number of gene copies to confer clinical resistance. Most interestingly, the microorgani
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