Journal Article

Molecular basis of intrinsic macrolide resistance in clinical isolates of <i>Mycobacterium fortuitum</i>

Kevin A. Nash, Yansheng Zhang, Barbara A. Brown-Elliott and Richard J. Wallace

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 55, issue 2, pages 170-177
Published in print February 2005 | ISSN: 0305-7453
Published online February 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh523
Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum

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Objectives: Some clinical isolates of Mycobacterium fortuitum are naturally resistant to macrolides, e.g. clarithromycin. Thus, the aim of this study was to identify the gene(s) conferring this resistance.

Methods: M. fortuitum ATCC 6841T DNA libraries were screened for plasmids that complemented the macrolide-susceptible phenotype of Mycobacterium smegmatis variant ermKO4 [erm(38)-negative]. Macrolide-resistant M. smegmatis transformants were selected on agar containing 128 mg/L erythromycin.

Results: Genetic complementation identified an M. fortuitum rRNA methylase gene, termed erm(39), 69% identical to erm(38) of M. smegmatis. In addition, erm(39) was found to be in the same chromosomal location as erm(38) in their respective hosts. Like erm(38), erm(39) conferred resistance (MIC >128 mg/L) to macrolide–lincosamide (ML) agents, but not to streptogramin B. Analysis of erm gene expression in M. fortuitum showed that ML agents increased erm(39) RNA levels, reaching a steady state level ∼20-fold higher than baseline. Screening of 32 M. fortuitum clinical isolates by PCR showed that all were positive for erm(39), irrespective of clarithromycin susceptibility. A majority of clarithromycin-susceptible (MIC ≤2 mg/L) isolates were postulated to carry a disabled erm(39) gene as they had a GTG→CTG mutation in the putative initiation codon of the erm(39) gene.

Conclusions: The similarity of the erm genes of M. smegmatis and M. fortuitum suggests that they were inherited from a common ancestor. Although the clinical impact of erm(39) on the therapeutic utility of clarithromycin is unclear, induction of this gene is consistent with the trailing end-points commonly seen during susceptibility testing of M. fortuitum isolates against macrolides.

Keywords: clarithromycin; rapidly growing mycobacteria; methylase; erm gene

Journal Article.  5485 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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