Antibiotic resistance by high-level intrinsic suppression of a frameshift mutation in an essential gene

In this data set are the WGS reads from two E. coli strains containing a frameshift mutation in rpoB. Frameshift mutations have been reported in rpoB, an essential gene encoding the beta-subunit of RNA polymerase, in rifampicin-resistant clinical isolates of Mycobacterium tuberculosis. These have never been experimentally validated, and no mechanisms of action have been proposed. We show that Escherichia coli with a +1-nt frameshift mutation centrally located in rpoB is viable and highly resistant to rifampicin. Spontaneous frameshifting occurs at a high rate on a heptanucleotide sequence downstream of the mutation, with production of active protein increased to 61-71% of wild-type level by a feedback mechanism that increases translation initiation. Accordingly, apparently lethal mutations can be viable and cause clinically relevant phenotypes, a finding that has broad significance for predictions of phenotype from genotype.