A frameshift mutation in the methyltransferase rlmN is associated with increased linezolid resistance in Mycobacterium tuberculosis

Abstract

Linezolid is a key component of treatment regimens for multidrug-resistant and extensively drug-resistant tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis (MTB). Resistance to linezolid in MTB has traditionally been attributed to mutations in the 23S rRNA (rrl) and ribosomal protein L3 (rplC), but only a fraction of clinically observed linezolid resistance is explained by mutations in these two genes. We report that an analysis of strains with paired whole-genome sequencing and linezolid minimum inhibitory concentration (MIC) phenotyping from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) reveals that a relatively common frameshift mutation in MTB methyltransferase rlmN (5.3% of assessed isolates) is significantly associated with increased linezolid MIC. In additional to statistical associations, we provide evolutionary evidence of homology to an established linezolid resistance mechanism in Staphylococcus aureus, and structural evidence that the frameshift mutation likely ablates rlmN methyltransferase functionality.