Using systems biology approaches to study a multidrug resistance network

Multidrug resistance (MDR), a phenomenon with impact in Human Health and in Agro-Food and Environmental Biotechnology, often results from the activation of drug efflux pumps, many times controlled at the transcriptional level. The complex transcriptional control of these genes has been on the focus of our research, guided by the information gathered in the YEASTRACT database. In this paper, the approach used to elucidate the transcriptional control of FLR1, encoding a Saccharomyces cerevisiae Drug:H+ Antiporter, in response to stress induced by the fungicide mancozeb is explained. The transcription regulatory network underlying FLR1 activation was defined based on experimental data. Subsequently, a mathematical model describing this network was built and its response to mancozeb stress in different genetic backgrounds was simulated, using the Genetic Network Analyzer (GNA) software. This approach allowed the identification of essential features of the transition from unstressed to fungicide stressed cells and to make new predictions on the dynamical behavior of the system, which were validated experimentally. This work provides a good example of the successful combination of experimental and computational approaches in a systems biology perspective.