title: 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.
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.
authors.affiliation: International Tuberculosis Research Center, Changwon, South Korea.
authors.forename: Taeksun
authors.initials: T
authors.lastname: Song
authors.forename: Yumi
authors.initials: Y
authors.lastname: Park
authors.forename: Isdore Chola
authors.initials: IC
authors.lastname: Shamputa
authors.forename: Sunghwa
authors.initials: S
authors.lastname: Seo
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Han-Seung
authors.initials: HS
authors.lastname: Jeon
authors.forename: Hongjo
authors.initials: H
authors.lastname: Choi
authors.forename: Myungsun
authors.initials: M
authors.lastname: Lee
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.forename: S Whitney
authors.initials: SW
authors.lastname: Barnes
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Serge
authors.initials: S
authors.lastname: Batalov
authors.forename: Karina
authors.initials: K
authors.lastname: Yusim
authors.forename: Shihai
authors.initials: S
authors.lastname: Feng
authors.forename: Chang-Shung
authors.initials: CS
authors.lastname: Tung
authors.forename: James
authors.initials: J
authors.lastname: Theiler
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.forename: Helena I M
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Katsuhiko S
authors.initials: KS
authors.lastname: Murakami
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000235:genetics* / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D020125:Mutation, Missense; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D012321:DNA-Directed RNA Polymerases; C105078:RNA polymerase beta subunit; D012293:Rifampin