Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex
| Autor: | Claudio U. Köser, Danesh Moradigaravand, Thomas Kohl, Philip W. Fowler, Timothy M Walker, Julian Parkhill, Thomas B. Schön, Kristian Ängeby, P. Jureen, Ivan Barilar, Florian P. Maurer, Sharon J. Peacock, Soenke Andres, Stefan Niemann, Matthias Merker, Erja Chryssanthou |
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| Přispěvatelé: | Apollo - University of Cambridge Repository, Kohl, Thomas A [0000-0002-1126-6803], Köser, Claudio [0000-0002-0232-846X], Parkhill, Julian [0000-0002-7069-5958], Peacock, Sharon [0000-0002-1718-2782] |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lineage (genetic) lcsh:QH426-470 030106 microbiology Antitubercular Agents lcsh:Medicine Drug resistance Clofazimine Intrinsic resistance Mycobacterium tuberculosis Inhibitory Concentration 50 03 medical and health sciences Antibiotic resistance Drug Resistance Bacterial Genotype Genetic variation Genetics medicine Diarylquinolines Molecular Biology Phylogeny Genetics (clinical) Ethambutol Medicinsk genetik biology Research lcsh:R Benign mutations biology.organism_classification 3. Good health lcsh:Genetics 030104 developmental biology Mycobacterium tuberculosis complex Mutation Molecular Medicine Genes MDR Medical Genetics medicine.drug |
| Zdroj: | Genome Medicine, Vol 12, Iss 1, Pp 1-8 (2020) Genome Medicine |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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