Fungal infections remain very difficult and expensive to treat. Antifungal development is hampered by lack of suitable targets that do not cause serious side effects in the host. An alternative to de novo drug development is to enhance existing therapies using synergistic agents. Iron chelators administered with certain antifungals have been found to improve the clearance of some fungal infections. However, mechanistic data are lacking on how these work, and why they sometimes do not, and iron depletion can also be damaging to the host. The aims of the current study are therefore 1) to find antifungals + iron chelator combinations that result in synergy when used to treat fungi; and 2) to use RNA-Seq and co-expression networks to analyse the synergistic response at the level of transcription and identify important mediators of synergy. The hypothesis is that by using transcriptome analysis during drug-chelator synergy we can identify differentially regulated pathways or process that we can target with new therapies that produce synergy without the need to administer chelators. Checkerboard assays were used to assess synergy between selected antifungals and iron chelators against Cryptococcus neoformans and C. gattii, with Saccharomyces cereviseae included for interactome construction. Significant synergy was uncommon and was only seen across all species when AMB was combined with lactoferrin, a milk protein with iron chelating properties. Transcriptional analysis by RNA-Seq was performed on S. cerevisiae treated with AMB only and AMB + lactoferrin (plus corresponding controls). Visualisation was done using Cytoscape and self organizing maps (SOMs). AMB treatment caused up-regulation of AFT1, a transcription factor involved in iron transport. AMB + lactoferrin halted the up-regulation of AFT1 and down-regulated genes involved in iron transport. The latter were co-expressed with YAP5, a transcription factor that co-ordinates expression of genes controlling the AFT1 nuclear localization. We are currently exploring the role of homologous factors in Cryptococcus using additional RNA-Seq assays.