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Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

Author

Listed:
  • Dimitrios Evangelopoulos

    (The Francis Crick Institute)

  • Gareth A. Prosser

    (The Francis Crick Institute
    The University of Manchester)

  • Angela Rodgers

    (The Francis Crick Institute)

  • Belinda M. Dagg

    (South Mimms)

  • Bhagwati Khatri

    (South Mimms)

  • Mei Mei Ho

    (South Mimms)

  • Maximiliano G. Gutierrez

    (The Francis Crick Institute)

  • Teresa Cortes

    (London School of Hygiene and Tropical Medicine)

  • Luiz Pedro S. Carvalho

    (The Francis Crick Institute)

Abstract

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations.

Suggested Citation

  • Dimitrios Evangelopoulos & Gareth A. Prosser & Angela Rodgers & Belinda M. Dagg & Bhagwati Khatri & Mei Mei Ho & Maximiliano G. Gutierrez & Teresa Cortes & Luiz Pedro S. Carvalho, 2019. "Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12074-z
    DOI: 10.1038/s41467-019-12074-z
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