The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis.
Mycobacterium tuberculosis
antimicrobial resistance
epistasis
evolution
fitness
fluoroquinolones
mycobacteria
Journal
Molecular biology and evolution
ISSN: 1537-1719
Titre abrégé: Mol Biol Evol
Pays: United States
ID NLM: 8501455
Informations de publication
Date de publication:
01 Jan 2020
01 Jan 2020
Historique:
pubmed:
19
9
2019
medline:
6
2
2020
entrez:
19
9
2019
Statut:
ppublish
Résumé
Fluoroquinolones (FQ) form the backbone in experimental treatment regimens against drug-susceptible tuberculosis. However, little is known on whether the genetic variation present in natural populations of Mycobacterium tuberculosis (Mtb) affects the evolution of FQ-resistance (FQ-R). To investigate this question, we used nine genetically distinct drug-susceptible clinical isolates of Mtb and measured their frequency of resistance to the FQ ofloxacin (OFX) in vitro. We found that the Mtb genetic background led to differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of magnitude and substantially modulated the observed mutational profiles for OFX-R. Further, in vitro assays showed that the genetic background also influenced the minimum inhibitory concentration and the fitness effect conferred by a given OFX-R mutation. To test the clinical relevance of our in vitro work, we surveyed the mutational profile for FQ-R in publicly available genomic sequences from clinical Mtb isolates, and found substantial Mtb lineage-dependent variability. Comparison of the clinical and the in vitro mutational profiles for FQ-R showed that 51% and 39% of the variability in the clinical frequency of FQ-R gyrA mutation events in Lineage 2 and Lineage 4 strains, respectively, can be attributed to how Mtb evolves FQ-R in vitro. As the Mtb genetic background strongly influenced the evolution of FQ-R in vitro, we conclude that the genetic background of Mtb also impacts the evolution of FQ-R in the clinic.
Identifiants
pubmed: 31532481
pii: 5571370
doi: 10.1093/molbev/msz214
pmc: PMC6984360
doi:
Substances chimiques
Anti-Bacterial Agents
0
Ofloxacin
A4P49JAZ9H
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
195-207Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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