Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase

Taeksun Song, Yumi Park, Isdore Chola Shamputa, Sunghwa Seo, Sun Young Lee, Han Seung Jeon, Hongjo Choi, Myungsun Lee, Richard J. Glynne, S. Whitney Barnes, John R. Walker, Serge Batalov, Karina Yusim, Shihai Feng, Chang Shung Tung, James Theiler, Laura E. Via, Helena I.M. Boshoff, Katsuhiko S. Murakami, Bette Korber & 2 others Clifton E. Barry, Sangnae Cho

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Rifampicin resistance, a defining attribute of multidrug-resistant tuberculosis, is conferred by mutations in the β subunit of RNA polymerase. Sequencing of rifampicin-resistant (RIF-R) clinical isolates of Mycobacterium tuberculosis revealed, in addition to RIF-R mutations, enrichment of potential compensatory mutations around the double-psi β-barrel domain of the β′ subunit comprising the catalytic site and the exit tunnel for newly synthesized RNA. Sequential introduction of the resistance allele followed by the compensatory allele in isogenic Mycobacterium smegmatis showed that these mutations respectively caused and compensated a starvation enhanced growth defect by altering RNA polymerase activity. While specific combinations of resistance and compensatory alleles converged in divergent lineages, other combinations recurred among related isolates suggesting transmission of compensated RIF-R strains. These findings suggest nutrient poor growth conditions impose larger selective pressure on RIF-R organisms that results in the selection of compensatory mutations in a domain involved in catalysis and starvation control of RNA polymerase transcription.

Original languageEnglish
Pages (from-to)1106-1119
Number of pages14
JournalMolecular Microbiology
Volume91
Issue number6
DOIs
Publication statusPublished - 2014 Mar 1

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DNA-Directed RNA Polymerases
Rifampin
Starvation
Mycobacterium tuberculosis
Costs and Cost Analysis
Food
Mutation
Alleles
Mycobacterium smegmatis
Multidrug-Resistant Tuberculosis
Growth
Catalysis
Catalytic Domain
RNA

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

Song, Taeksun ; Park, Yumi ; Shamputa, Isdore Chola ; Seo, Sunghwa ; Lee, Sun Young ; Jeon, Han Seung ; Choi, Hongjo ; Lee, Myungsun ; Glynne, Richard J. ; Barnes, S. Whitney ; Walker, John R. ; Batalov, Serge ; Yusim, Karina ; Feng, Shihai ; Tung, Chang Shung ; Theiler, James ; Via, Laura E. ; Boshoff, Helena I.M. ; Murakami, Katsuhiko S. ; Korber, Bette ; Barry, Clifton E. ; Cho, Sangnae. / Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase. In: Molecular Microbiology. 2014 ; Vol. 91, No. 6. pp. 1106-1119.
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abstract = "Rifampicin resistance, a defining attribute of multidrug-resistant tuberculosis, is conferred by mutations in the β subunit of RNA polymerase. Sequencing of rifampicin-resistant (RIF-R) clinical isolates of Mycobacterium tuberculosis revealed, in addition to RIF-R mutations, enrichment of potential compensatory mutations around the double-psi β-barrel domain of the β′ subunit comprising the catalytic site and the exit tunnel for newly synthesized RNA. Sequential introduction of the resistance allele followed by the compensatory allele in isogenic Mycobacterium smegmatis showed that these mutations respectively caused and compensated a starvation enhanced growth defect by altering RNA polymerase activity. While specific combinations of resistance and compensatory alleles converged in divergent lineages, other combinations recurred among related isolates suggesting transmission of compensated RIF-R strains. These findings suggest nutrient poor growth conditions impose larger selective pressure on RIF-R organisms that results in the selection of compensatory mutations in a domain involved in catalysis and starvation control of RNA polymerase transcription.",
author = "Taeksun Song and Yumi Park and Shamputa, {Isdore Chola} and Sunghwa Seo and Lee, {Sun Young} and Jeon, {Han Seung} and Hongjo Choi and Myungsun Lee and Glynne, {Richard J.} and Barnes, {S. Whitney} and Walker, {John R.} and Serge Batalov and Karina Yusim and Shihai Feng and Tung, {Chang Shung} and James Theiler and Via, {Laura E.} and Boshoff, {Helena I.M.} and Murakami, {Katsuhiko S.} and Bette Korber and Barry, {Clifton E.} and Sangnae Cho",
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Song, T, Park, Y, Shamputa, IC, Seo, S, Lee, SY, Jeon, HS, Choi, H, Lee, M, Glynne, RJ, Barnes, SW, Walker, JR, Batalov, S, Yusim, K, Feng, S, Tung, CS, Theiler, J, Via, LE, Boshoff, HIM, Murakami, KS, Korber, B, Barry, CE & Cho, S 2014, 'Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase', Molecular Microbiology, vol. 91, no. 6, pp. 1106-1119. https://doi.org/10.1111/mmi.12520

Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase. / Song, Taeksun; Park, Yumi; Shamputa, Isdore Chola; Seo, Sunghwa; Lee, Sun Young; Jeon, Han Seung; Choi, Hongjo; Lee, Myungsun; Glynne, Richard J.; Barnes, S. Whitney; Walker, John R.; Batalov, Serge; Yusim, Karina; Feng, Shihai; Tung, Chang Shung; Theiler, James; Via, Laura E.; Boshoff, Helena I.M.; Murakami, Katsuhiko S.; Korber, Bette; Barry, Clifton E.; Cho, Sangnae.

In: Molecular Microbiology, Vol. 91, No. 6, 01.03.2014, p. 1106-1119.

Research output: Contribution to journalArticle

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T1 - Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase

AU - Song, Taeksun

AU - Park, Yumi

AU - Shamputa, Isdore Chola

AU - Seo, Sunghwa

AU - Lee, Sun Young

AU - Jeon, Han Seung

AU - Choi, Hongjo

AU - Lee, Myungsun

AU - Glynne, Richard J.

AU - Barnes, S. Whitney

AU - Walker, John R.

AU - Batalov, Serge

AU - Yusim, Karina

AU - Feng, Shihai

AU - Tung, Chang Shung

AU - Theiler, James

AU - Via, Laura E.

AU - Boshoff, Helena I.M.

AU - Murakami, Katsuhiko S.

AU - Korber, Bette

AU - Barry, Clifton E.

AU - Cho, Sangnae

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Rifampicin resistance, a defining attribute of multidrug-resistant tuberculosis, is conferred by mutations in the β subunit of RNA polymerase. Sequencing of rifampicin-resistant (RIF-R) clinical isolates of Mycobacterium tuberculosis revealed, in addition to RIF-R mutations, enrichment of potential compensatory mutations around the double-psi β-barrel domain of the β′ subunit comprising the catalytic site and the exit tunnel for newly synthesized RNA. Sequential introduction of the resistance allele followed by the compensatory allele in isogenic Mycobacterium smegmatis showed that these mutations respectively caused and compensated a starvation enhanced growth defect by altering RNA polymerase activity. While specific combinations of resistance and compensatory alleles converged in divergent lineages, other combinations recurred among related isolates suggesting transmission of compensated RIF-R strains. These findings suggest nutrient poor growth conditions impose larger selective pressure on RIF-R organisms that results in the selection of compensatory mutations in a domain involved in catalysis and starvation control of RNA polymerase transcription.

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