Mycobacterium tuberculosis- credit: NIH-NIAID (CC-BY)
Continuing with our month-long celebration of Nature Genetics 25th anniversary, I have chosen to highlight a study by Sarah Fortune and colleagues estimating mutation rate differences between different lineages of Mycobacterium tuberculosis published in June 2013.
Multidrug resistance in M. tuberculosis is a global problem, and understanding the origins and dynamics of the emergence of resistance is an important scientific and public health endeavor.
Building on their previous work that used whole genome sequencing to estimate mutation rates of M. tuberculosis during latent infection, the authors then went on to study the rate at which different strains acquire drug resistance mutations. Using classical fluctuation tests and measuring rifampicin resistance in both clinical and laboratory isolates, they determined the mutation rates for strains from lineage 2 and lineage 4, observing an order of magnitude difference between them, with lineage 2 having the higher rate. These lineage 2 strains also acquired resistance to other antibiotics (ethambutol, isoniazid) at a higher rate than lineage 4 strains.
The authors then sought to relate the in vitro data to the in vivo infection environment. They analyzed whole-genome sequences from a lineage 4 outbreak and determined the base substitution rate; the in vivo data were in concordance with the in vitro per-day mutation rate.
Finally, the authors took these data and developed a simulation model of the evolution of drug resistance during infection in a human host. They simulate the emergence of multidrug resistance and show that in the model, individuals infected with lineage 2 strains had a substantially higher risk of acquiring multidrug resistance mutations.
Using a combination of in vitro, clinical and simulated data, Ford et al. contributed to our understanding of the emergence of multidrug resistance, highlighting the differences between strains and underscoring the importance of timely and sufficient treatment.