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JAC Advance Access originally published online on December 8, 2004
Journal of Antimicrobial Chemotherapy 2005 55(2):170-177; doi:10.1093/jac/dkh523
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JAC vol.55 no.2 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved

Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum

Kevin A. Nash1,*, Yansheng Zhang2, Barbara A. Brown-Elliott2 and Richard J. Wallace, Jr2

1 Department of Pathology, University of Southern California, and Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA; 2 Department of Microbiology, The University of Texas Health Center, Tyler, TX, USA

* Corresponding author. Tel: +1-323-669-5670; Fax: +1-323-668-7989; Email: kanash{at}usc.edu

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


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