Nishikawa Joy L, Boeszoermenyi Andras, Vale-Silva Luis A, Torelli Riccardo, Posteraro Brunella, Sohn Yoo-Jin, Ji Fei, Gelev Vladimir, Sanglard Dominique, Sanguinetti Maurizio, Sadreyev Ruslan I, Mukherjee Goutam, Bhyravabhotla Jayaram, Buhrlage Sara J, Gray Nathanael S, Wagner Gerhard, Näär Anders M, Arthanari Haribabu (2016), Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction., in Nature
, 530(7591), 485-9.
Asner Sandra A, Giulieri Stefano, Diezi Manuel, Marchetti Oscar, Sanglard Dominique (2015), Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy., in Antimicrobial agents and chemotherapy
, 59(12), 7715-22.
Sanglard Dominique, Coste Alix T (2015), Activity of Isavuconazole and Other Azoles against Candida Clinical Isolates and Yeast Model Systems with Known Azole Resistance Mechanisms., in Antimicrobial agents and chemotherapy
, 60(1), 229-38.
Delarze Eric, Sanglard Dominique (2015), Defining the frontiers between antifungal resistance, tolerance and the concept of persistence., in Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
, 23, 12-9.
Cowen Leah E, Sanglard Dominique, Howard Susan J, Rogers P David, Perlin David S (2015), Mechanisms of Antifungal Drug Resistance., in Cold Spring Harbor perspectives in medicine
, 5(7), 019752-019752.
Jensen Rasmus Hare, Astvad Karen Marie Thyssen, Silva Luis Vale, Sanglard Dominique, Jørgensen Rene, Nielsen Kristian Fog, Mathiasen Estella Glintborg, Doroudian Ghazalel, Perlin David Scott, Arendrup Maiken Cavling (2015), Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations., in The Journal of antimicrobial chemotherapy
, 70(9), 2551-5.
Vale-Silva Luis A, Sanglard Dominique (2015), Tipping the balance both ways: drug resistance and virulence in Candida glabrata., in FEMS yeast research
, 15(4), 025-025.
Infections caused by fungal pathogens belonging to Candida spp. (C. albicans and C. glabrata) are still a challenge to the medical practice. Despite available antifungal fungal diseases remains a threat to human health and especially in the population of immuno-compromised patients. As a consequence of antifungal treatment in patients and exposure of the pathogens to antifungals, resistance can develop and compromise the success of the therapy. Antifungal resistance is mediated by multiple mechanisms and, while they enable fungal survival under drug pressure in the host, can lead to fitness costs. In C. glabrata, mutations in the transcription factor CgPDR1 (so called GOF mutations for gain-of-function) are participating to the upregulation of the ABC transporter CDR1 which is involved in azole resistance. The occurrence of the same mutations results in enhanced virulence and fitness in animal models. In C. albicans, mutations in factors involved in drug resistance have on the opposite neutral of even negative impact on virulence, however compensation mechanisms can operate to correct negative effects. We have shown in C. glabrata that two CgPDR1-regulated genes including CDR1 and a mitochondrial gene (PUP1) could be made partially responsible for this virulence attribute. Our recent work has revealed that CgPDR1 could also mediate a decreased adherence of C. glabrata to specific cells of the immune system (mice bone marrow derived macrophages, BMDMs) but without altering C. glabrata survival within BMDMs after phagocytosis. Altered adherence step could constitute an escape mechanism by which increased virulence in mice can be further established. Interestingly, the CgPDR1-dependent decreased adherence is not observed in all C. glabrata clinical isolates, thus highlighting that specific CgPDR1 target genes, most likely encoding cell wall proteins, are absent (or mutated) in specific C. glabrata genomes. In the first part of this research proposal, we will address whether the adherence phenotype is conserved among different host cell types including cells of the innate immune system, epithelial and endothelial cells. Next, we will address the identity of specific genes that are participating to the decreased adherence of C. glabrata to specific cell types. For this purpose, several approaches will be used, including proteomic, transcriptomic and genomic methods. We will then establish a panel of C. glabrata isolates taken from our clinical collection with a CgPDR1-dependent adherence phenotype. Two groups will be created: one with low and the other with high adherence to host cells. These isolates will be then systematically investigated in order to identify the genetic basis for the differences between the two yeast groups. Transcriptional and genomic data will be matched in these analyses, however the group of cell wall genes will be more specifically targeted. Candidate genes would be then systematically investigated and a tetracycline-regulatable system will be used to assess their role in host cell adherence. In a second part of this research proposal, we will address by transcriptomic and genomic approaches how C. albicans can compensate for the decreased virulence caused by mutation in mediators of antifungal resistance. We will here use a clinical isolate with a known mutation in a gene involved in sterol biosynthesis (ERG3) but exhibiting no fitness costs as opposed to laboratory isolates with the same mutation.In conclusion, our results are expected to highlight the role of specific Candida genes, which intriguingly associate antifungal resistance with interactions to host cells and which contribute to pathogenesis of these fungi which are still the cause of a majority of fungal diseases in human.