title: Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease.
abstract: Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosis infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellulare lung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5 Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in M. tuberculosis Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5 drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5 mutations are associated with modest 2- to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpE mutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellulare lung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5 variants and microbiological relapse.
authors.affiliation: University of Regina, Department of Biology, Regina, Saskatchewan, Canada David.Alexander@gov.mb.ca.
authors.forename: David C
authors.initials: DC
authors.lastname: Alexander
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Microbiology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: Ravikiran
authors.initials: R
authors.lastname: Vasireddy
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Microbiology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Vasireddy
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: Julie V
authors.initials: JV
authors.lastname: Philley
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Microbiology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Brown-Elliott
authors.affiliation: University of Regina, Department of Biology, Regina, Saskatchewan, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Perry
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Griffith
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Microbiology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.|The Mycobacteria/Nocardia Research Laboratory, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: Jeana L
authors.initials: JL
authors.lastname: Benwill
authors.affiliation: University of Regina, Department of Biology, Regina, Saskatchewan, Canada.
authors.forename: Andrew D S
authors.initials: AD
authors.lastname: Cameron
authors.affiliation: The Mycobacteria/Nocardia Research Laboratory, Department of Microbiology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.|The Mycobacteria/Nocardia Research Laboratory, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wallace
mesh_terms: D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use*; D064687:Diarylquinolines / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D005260:Female; D016680:Genome, Bacterial; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D020125:Mutation, Missense; D015269:Mycobacterium avium Complex / Q000235:genetics* / Q000302:isolation & purification; D012008:Recurrence; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D014157:Transcription Factors; C493870:bedaquiline
keywords: Mycobacterium avium; Mycobacterium intracellulare; antibiotic resistance; bedaquiline