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

Dimitrios Evangelopoulos, Gareth A. Prosser, Angela Rodgers, Belinda M. Dagg, Bhagwati Khatri, Mei Mei Ho, Maximiliano G. Gutierrez, Teresa Cortes and Luiz Pedro S. Carvalho ()
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Dimitrios Evangelopoulos: The Francis Crick Institute
Gareth A. Prosser: The Francis Crick Institute
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

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12074-z

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