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Phylogenetically in...
Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex
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- Merker, Matthias (author)
- German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany
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- Kohl, Thomas A. (author)
- Karolinska Institutet
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- Barilar, Ivan (author)
- German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany
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- Andres, Soenke (author)
- Natl and WHO Supranat Reference Ctr Mycobacteria, Germany
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- Fowler, Philip W. (author)
- Univ Oxford, England
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- Chryssanthou, Erja (author)
- Karolinska Institutet
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- Angeby, Kristian (author)
- Karolinska Inst, Sweden
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- Jureen, Pontus (author)
- Publ Hlth Agcy Sweden, Sweden
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- Moradigaravand, Danesh (author)
- Univ Birmingham, England
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- Parkhill, Julian (author)
- Univ Cambridge, England
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- Peacock, Sharon J. (author)
- Univ Cambridge, England
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- Schön, Thomas (author)
- Linköpings universitet,Avdelningen för inflammation och infektion,Medicinska fakulteten,Kalmar Cty Hosp, Sweden
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- Maurer, Florian P. (author)
- Natl and WHO Supranat Reference Ctr Mycobacteria, Germany; Univ Med Ctr Hamburg Eppendorf, Germany
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- Walker, Timothy (author)
- Univ Oxford, England
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- Koser, Claudio (author)
- Univ Cambridge, England
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- Niemann, Stefan (author)
- German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany
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(creator_code:org_t)
- 2020-03-06
- 2020
- English.
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In: Genome Medicine. - : BMC. - 1756-994X. ; 12:1
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Abstract
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- Background A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). Methods We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cut-off values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
- NATURVETENSKAP -- Biologi -- Evolutionsbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Evolutionary Biology (hsv//eng)
Keyword
- Mycobacterium tuberculosis; Drug resistance; Benign mutations; Intrinsic resistance
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Merker, Matthias
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Kohl, Thomas A.
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Barilar, Ivan
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Andres, Soenke
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Fowler, Philip W ...
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Chryssanthou, Er ...
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show more...
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Angeby, Kristian
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Jureen, Pontus
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Moradigaravand, ...
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Parkhill, Julian
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Peacock, Sharon ...
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Schön, Thomas
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Maurer, Florian ...
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Walker, Timothy
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Koser, Claudio
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Niemann, Stefan
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Microbiology in ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Evolutionary Bio ...
- Articles in the publication
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Genome Medicine
- By the university
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Linköping University
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Karolinska Institutet