edoc

The genetic background modulates the evolution of fluoroquinolone-resistance in Mycobacterium tuberculosis

Castro, Rhastin A. D. and Ross, Amanda and Kamwela, Lujeko and Reinhard, Miriam and Loiseau, Chloé and Feldmann, Julia and Borrell, Sonia and Trauner, Andrej and Gagneux, Sebastien. (2020) The genetic background modulates the evolution of fluoroquinolone-resistance in Mycobacterium tuberculosis. Molecular biology and evolution, 37 (1). pp. 195-207.

[img] PDF - Published Version
Available under License CC BY (Attribution).

1298Kb

Official URL: https://edoc.unibas.ch/75536/

Downloads: Statistics Overview

Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Biostatistics > Biostatistics Frequentist Modelling
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Tuberculosis Research (Gagneux)
UniBasel Contributors:Castro, Rhastin and Ross, Amanda and Kamwela, Lujeko and Reinhard, Miriam and Loiseau, Chloé Marie and Feldmann, Julia and Trauner, Andrej and Gagneux, Sebastien
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
ISSN:0737-4038
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:05 Mar 2020 08:22
Deposited On:05 Mar 2020 08:22

Repository Staff Only: item control page