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The Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis is Modulated by the Genetic Background

Rhastin A. D. Castro, Amanda Ross, Lujeko Kamwela, Miriam Reinhard, Chloé Loiseau, Julia Feldmann, Sonia Borrell, View ORCID ProfileAndrej Trauner, Sebastien Gagneux
doi: https://doi.org/10.1101/659045
Rhastin A. D. Castro
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Amanda Ross
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Lujeko Kamwela
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Miriam Reinhard
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Chloé Loiseau
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Julia Feldmann
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Sonia Borrell
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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Andrej Trauner
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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  • ORCID record for Andrej Trauner
  • For correspondence: sebastien.gagneux@swisstph.ch andrej.trauner@swisstph.ch
Sebastien Gagneux
1Swiss Tropical and Public Health Institute, Basel, Switzerland
2University of Basel, Basel, Switzerland
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  • For correspondence: sebastien.gagneux@swisstph.ch andrej.trauner@swisstph.ch
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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 a set of Mtb strains that included nine genetically distinct drug-susceptible clinical isolates, 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 45% and 19% of the variability in the clinical frequency of FQ-R gyrA mutations 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.

Significance Newer generations of fluoroquinolones form the backbone in many experimental treatment regimens against M. tuberculosis (Mtb). While the genetic variation in natural populations of Mtb can influence resistance evolution to multiple different antibiotics, it is unclear whether it modulates fluoroquinolone-resistance evolution as well. Using a combination of in vitro assays coupled with genomic analysis of clinical isolates, we provide the first evidence illustrating the Mtb genetic background’s substantial role in fluoroquinolone-resistance evolution, and highlight the importance of bacterial genetics when studying the prevalence of fluoroquinolone-resistance in Mtb. Our work may provide insights into how to maximize the timespan in which fluoroquinolones remain effective in clinical settings, whether as part of current standardized regimens, or in new regimens against Mtb.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 03, 2019.
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The Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis is Modulated by the Genetic Background
Rhastin A. D. Castro, Amanda Ross, Lujeko Kamwela, Miriam Reinhard, Chloé Loiseau, Julia Feldmann, Sonia Borrell, Andrej Trauner, Sebastien Gagneux
bioRxiv 659045; doi: https://doi.org/10.1101/659045
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The Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis is Modulated by the Genetic Background
Rhastin A. D. Castro, Amanda Ross, Lujeko Kamwela, Miriam Reinhard, Chloé Loiseau, Julia Feldmann, Sonia Borrell, Andrej Trauner, Sebastien Gagneux
bioRxiv 659045; doi: https://doi.org/10.1101/659045

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