Emergence of Inducible Macrolide Resistance in Mycobacterium chelonae Due to Broad-Host-Range Plasmid and Chromosomal Variants of the Novel 23S rRNA Methylase Gene, (55).

Macrolides are a mainstay of therapy for infections due to nontuberculous mycobacteria (NTM). Among rapidly growing mycobacteria (RGM), inducible macrolide resistance is associated with four chromosomal 23S rRNA methylase () genes. Beginning in 2018, we detected high-level inducible clarithromycin resistance (MICs of ≥16μg/mL) in clinical isolates of Mycobacterium chelonae, an RGM species not previously known to contain genes. Using whole-genome sequencing, we identified a novel plasmid-mediated gene. This gene, designated (55), exhibits <65% amino acid identity to previously described RGM genes. Two additional chromosomal (55) alleles, with sequence identities of 81% to 86% to (55), were also identified and designated (55) and (55). The (55) is part of a transposon. The (55) allele variant is located on a putative 137-kb conjugative plasmid, pMchErm55. Evaluation of 133 consecutive isolates from 2020 to 2022 revealed 5 (3.8%) with (55). The e(55) gene was also identified in public data sets of two emerging pathogenic pigmented RGM species: Mycobacterium iranicum and Mycobacterium obuense, dating back to 2008. In both species, the gene appeared to be present on plasmids homologous to pMchErm55. Plasmid-mediated macrolide resistance, not described previously for any NTM species, appears to have spread to multiple RGM species. This has important implications for antimicrobial susceptibility guidelines and treatment of RGM infections. Further spread could present serious consequences for treatment of other macrolide-susceptible RGM. Additional studies are needed to determine the transmissibility of pMchErm55 and the distribution of (55) among other RGM species.