title: Mycobacterial mistranslation is necessary and sufficient for rifampicin phenotypic resistance.
abstract: Errors are inherent in all biological systems. Errors in protein translation are particularly frequent giving rise to a collection of protein quasi-species, the diversity of which will vary according to the error rate. As mistranslation rates rise, these new proteins could produce new phenotypes, although none have been identified to date. Here, we find that mycobacteria substitute glutamate for glutamine and aspartate for asparagine at high rates under specific growth conditions. Increasing the substitution rate results in remarkable phenotypic resistance to rifampicin, whereas decreasing mistranslation produces increased susceptibility to the antibiotic. These phenotypic changes are reflected in differential susceptibility of RNA polymerase to the drug. We propose that altering translational fidelity represents a unique form of environmental adaptation.
authors.affiliation: Centre for Infectious Diseases Research, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Babak
authors.initials: B
authors.lastname: Javid
authors.forename: Flavia
authors.initials: F
authors.lastname: Sorrentino
authors.forename: Melody
authors.initials: M
authors.lastname: Toosky
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Pinkham
authors.forename: Nina
authors.initials: N
authors.lastname: Jain
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Pan
authors.forename: Padraig
authors.initials: P
authors.lastname: Deighan
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
mesh_terms: D000595:Amino Acid Sequence; D000904:Antibiotics, Antitubercular / Q000737:chemistry*; D001216:Asparagine / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry; D024881:Drug Resistance, Bacterial; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D008969:Molecular Sequence Data; D009154:Mutation; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000235:genetics*; D010641:Phenotype; D014176:Protein Biosynthesis; D040901:Proteomics; D011995:Recombination, Genetic; D012293:Rifampin / Q000737:chemistry*
chemical_list: D000904:Antibiotics, Antitubercular; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D001216:Asparagine; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin
keywords: drug tolerance; persisters