Published on December 14, 2018 | Updated on December 14, 2018


Microevolution and fitness modulation of Mycobacterium tuberculosis exposed to two-drug combinations: in vitro experiment and mathematical modeling

Co-leaders: Oana Dumitrescu (CIRI) & Sylvain Goutellet (LBBE)

Tuberculosis (TB) remains one of the leading causes of death by infectious disease. Management of drug-susceptible, pulmonary tuberculosis treatment is tailored by WHO international guidelines and based on six-month, multi-drug therapy. The dosage design of current TB drug regimens has been based on clinical data, as well as cost considerations from the 1960-70s. Since then, it has not been updated to optimize the antibacterial effect of drug combinations or the suppression of drug resistance. Also, while multi-drug therapy is the standard-of-care for TB, virtually all pre-clinical studies have focused on the antibacterial effect of single agents.
Inappropriate drug regimen and dosing lead to treatment failure which is associated with increased risk of de novo generation of multidrug resistant M. tuberculosis (MTB). Besides, suboptimal treatment can facilitate genetic selection of clonal variants within a single patient, thus providing increased fitness and enhanced capacity to cause disease. There is both experimental and clinical evidence that MTB strains from different lineages vary in their capacity to cause disease and acquire drug resistance. Specifically, MTB strains belonging to the East Asian lineage (which includes the Beijing family) have been associated with increased risk of drug resistance relative to strains from the Euro-American lineage. A study confirmed that MTB strains belonging to the East Asian lineage display a higher rate of acquisition of drug resistance and an overall higher mutation rate than that of strains from the Euro-American lineage, even when exposed to the anti-TB agent rifampicin. While mutations conferring drug resistance have long been thought to reduce fitness or virulence of MTB, studies have shown that clinical strains of MTB resistant to rifampicin may have no fitness defect.
Altogether these findings raise the question of whether drug combinations and dosages recommended by the WHO can fit to all situations regardless to the phylogeographic lineages at diagnosis.
The objectives of our project are:
- To measure the in vitro antibacterial effect of rifampicin+isoniazid combination against MTB strains from different lineages
- To detect SNP acquisition during treatment and analyse the genetic changes observed in bacterial subpopulations.
- To characterize the role of identified SNP in fitness modulation
- To perform mathematical modeling of experimental data in order to quantify the combined effect of drugs and describe its description in terms of synergy/antagonism.

Co-leaders : Oana Dumitrescu, team "Pathogenèse des infections à staphylocoques" (CIRI) & Sylvain Goutelle, team "Evaluation et Modélisation des Effets Thérapeutiques" (LBBE).
Project duration:
2 years
Financing :
Post-doctoral fellowship & consumable money
Post-doctoral fellow :
Charlotte Genestet