Widespread macrolide resistance among rapidly growing mycobacteria due to plasmids containing erm(55)

Macrolides (clarithromycin and azithromycin) are a mainstay of therapy for infections caused by rapidly growing mycobacteria (RGM). Historically, macrolide resistance in RGM species is associated with mutations in the 23S rRNA gene and chromosomal erythromycin ribosome methylase (erm) genes. We recently described macrolide resistance in the RGM species, Mycobacterium chelonae, due to a novel, plasmid-encoded erm(55) gene. For this study, we expanded our search to pigmented RGM species. Clinical isolates from two U.S. reference laboratories were screened. Isolates were collected between 1997 and 2024 from diverse clinical sites and multiple geographic locales. Here, we describe the genetic diversity of 30 erm(55)-containing plasmids from six different RGM species. The plasmids share a common 126 kb backbone but, due to insertions and deletions, vary in size from 119 to 173 kb. Six plasmids carry heavy metal resistance operons in addition to erm(55). These results imply that erm(55)-containing plasmids are highly promiscuous, conjugative, and have been spreading unnoticed for decades. They are present in M. chelonae as well as pathogenic pigmented RGM species, including M. bacteremicum, M. grossiae, M. iranicum, M. neoaurum and M. obuense. Their spread to other RGM species seems inevitable and has serious implications for antimicrobial therapy.