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

被引:96
作者
Nash, KA [1 ]
Zhang, YS
Brown-Elliott, BA
Wallace, RJ
机构
[1] Univ So Calif, Dept Pathol, Los Angeles, CA 90089 USA
[2] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA
[3] Univ Texas Hlth Ctr, Dept Microbiol, Tyler, TX 75710 USA
关键词
clarithromycin; rapidly growing mycobacteria; methylase; erm gene;
D O I
10.1093/jac/dkh523
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
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 6841(T) 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 similar to20-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 less than or equal to2 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.
引用
收藏
页码:170 / 177
页数:8
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