On the evolution of azole resistance in Aspergillus fumigatus

During the last decade azole resistance has increasingly been reported in Aspergillus fumigatus, which is a fungal pathogen involved in the vast majority of invasive aspergillosis infections in humans, and is now a global public health concern. Antifungal azoles, especially triazoles, are the drugs of choice for medical treatment. However, this treatment is hampered by the emergence of multi-azole resistant A. fumigatus isolates, especially the highly resistant variants TR34/L98H and TR46 /Y121F/T289A. Therefore, to control this disease, it is essential to elucidate by what mechanisms resistance emerges, how resistance spreads and how resistant genotypes persist in environments without azoles. The presented thesis shows the relevance of the life cycle of A. fumigatus to the development of azole resistance and possible evolutionary routes that lead to it. The work highlights the importance of fungal biology and evolution towards understanding the development of azole resistance in fungi. We conclude that azole resistance in A. fumigatus is a consequence of selection pressure by azole in the environment on the genetic variation generated via various aspects in the A. fumigatus life cycle. This thesis also introduces an experimental evolution approach to study the dynamics and mechanisms of the evolution of azole resistance. In addition, we investigate what condition can lead an environment to be a possible hotspot for the development of resistance. Finally, we link this to the potential conditions under which resistance can emerge and spread in the lungs of humans and how this depends on the specific azole used.