Fitness Effect of Drug Resistance
We use a combination of experimental evolution, molecular epidemiology, comparative genome sequencing of clinical strains and systems biology to investigate the emergence, evolution and impact of drug resistance on the MTBC. In the past, we were able to show that different drug resistance-conferring mutations are associated with different effects on strain fitness. These differences are reflected in the relative abundance of each mutation in the clinic.
Compensation and Other Epistatic Interactions
In recent years, it has become clear that the molecular mechanisms of resistance to antibiotics are complex, and that many of the mutations involved can interact epistatically. We have been exploring how epistatic interactions between different drug resistance-conferring mutations, compensatory mutations and the strain genetic background influence the fitness of multidrug-resistant strains. Starting from the observation that drug-resistant strains isolated from patients tend to be fitter than strains generated in the laboratory, we were able to identify compensatory mutations in the RNA polymerase which mitigate some of the negative effects associated with rifampicin resistance in the MTBC.
Ongoing work in the Unit explores the cost of drug resistance and the evolutionary processes that shape drug-resistant strains. Our hope is to be able to explain why, and possibly predict which resistant genotypes give rise to highly transmissible drug-resistant TB.