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Antibiotic resistance by high-level intrinsic suppression of a frameshift mutation in an essential gene
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0001-8457-7699
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-7456-9182
2020 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 6, p. 3185-3191Article in journal (Refereed) Published
Abstract [en]

A fundamental feature of life is that ribosomes read the genetic code in messenger RNA (mRNA) as triplets of nucleotides in a single reading frame. Mutations that shift the reading frame generally cause gene inactivation and in essential genes cause loss of viability. Here we report and characterize a +1-nt frameshift mutation, centrally located in rpoB, an essential gene encoding the beta-subunit of RNA polymerase. Mutant Escherichia coli carrying this mutation are viable and highly resistant to rifampicin. Genetic and proteomic experiments reveal a very high rate (5%) of spontaneous frameshift suppression occurring on a heptanucleotide sequence downstream of the mutation. Production of active protein is stimulated to 61-71% of wild-type level by a feedback mechanism increasing translation initiation. The phenomenon described here could have broad significance for predictions of phenotype from genotype. Several frameshift mutations have been reported in rpoB in rifampicin-resistant clinical isolates of Mycobacterium tuberculosis (Mtb). These mutations have never been experimentally validated, and no mechanisms of action have been proposed. This work shows that frameshift mutations in rpoB can be a mutational mechanism generating antibiotic resistance. Our analysis further suggests that genetic elements supporting productive frame-shifting could rapidly evolve de novo, even in essential genes.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2020. Vol. 117, no 6, p. 3185-3191
Keywords [en]
rpoB, frameshift suppression, antibiotic resistance, evolution, gene regulation
National Category
Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-407505DOI: 10.1073/pnas.1919390117ISI: 000513898000061PubMedID: 31992637OAI: oai:DiVA.org:uu-407505DiVA, id: diva2:1416974
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved

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Huseby, Douglas LBrandis, GerritPraski Alzrigat, LisaHughes, Diarmaid

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