P68

Drug-resistant tuberculosis continues to be a public health crisis, challenging the existing treatment regimens with about half a million new cases, annually. The implementation of new regimens is not outpacing the rate of resistance development. To understand resistance evolution, we established several in vitro models for Mycobacterium tuberculosis complex (Mtbc) strains employing principles of evolutionary medicine. Evolutionary medicine applies natural selection concepts to understand and improve medical research. Exerting Next Generation Sequencing technology and in vitro assays, we gathered insights into resistance and resilience mechanisms, which may be used to advance evolutionary-informed treatment strategies. Further, we aim to understand the impact of the genetic background of clinical Mtbc strains on drug resilience development.

First results showed that resistance in Mtbc strains is selected at levels, far below the MIC of the wild-type. This indicated a large mutant selection window, which also varies for different resistance associated variants even within the same gene. Transcriptional profiling of selected mutant clones allowed a further elucidation of resistance mechanisms. To analyze the role of drug resilience in resistance development of Mtbc strains, we established in vitro models analyzing clinical Mtbc strains in response to key TB drugs. Ultimately, we hope to find intervention opportunities to curtail this resilience and resistance evolution.

By advancing our knowledge of resistance evolution, these models have the potential to expand treatment strategies utilizing evolutionary-informed approaches.