Candida; antifungal resitance; gene regulation; multidrug transporters; virulence; transcriptional activators
Lohberger A Coste AT Sanglard D (2013), Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence, in Eukaryotic Cell
, 13, 127-142.
Vale-Silva L., Ischer F., Leibundgut-Landmann S., Sanglard D. (2013), Gain of function mutations in CgPDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells, in Infect Immun
, in press, xxx.
Silva L. V., Sanguinetti M., Vandeputte P., Torelli R., Rochat B., Sanglard D. (2013), Milbemycins: more than efflux inhibitors for fungal pathogens, in Antimicrob Agents Chemother
, 57, 873-86.
Ferrari S, Sanguinetti M, Torelli R, Posteraro B, Sanglard D (2011), Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata, in PLOS ONE
, 6(3), e17589-e17589.
Vandeputte P, Ischer F, Sanglard D, Coste AT (2011), In Vivo Systematic Analysis of Candida albicans Zn2-Cys6 Transcription Factors Mutants for Mice Organ Colonization, in PLOS ONE
, 6(10), e26962-e26962.
Ferrari S, Sanguinetti M, De Bernardis F, Torelli R, Posteraro B, Vandeputte P, Sanglard D (2011), Loss of Mitochondrial Functions Associated with Azole Resistance in Candida glabrata Results in Enhanced Virulence in Mice, in ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
, 55(5), 1852-1860.
Puri N, Manoharlal R, Sharma M, Sanglard D, Prasad R (2011), Overcoming the heterologous bias: An in vivo functional analysis of multidrug efflux transporter, CgCdr1p in matched pair clinical isolates of Candida glabrata, in BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
, 404(1), 357-363.
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 re-mains a threat to human health and especially in the population of immuno-compromised pa-tients. 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. For the fungal pathogen, while development of resistance is associated with the persistence of the infection in the host, the adaptive mechanisms behind resistance development can significantly alter the capacities that are necessary to survive in the host, a notion also known under the term of “fit-ness cost”. It is generally believed that development of antifungal resistance is associated with fitness costs in microbial pathogens which results in their decreased virulence. Our recent work has revealed in C. glabrata the unexpected association between antifungal resistance de-velopment and gain of fitness (and virulence) in animal models. Therefore our results challenge the dogma existing between these two phenomenons. In this research proposal, a detailed molecular analysis of the factors involved in the associa-tion between fitness and antifungal resistance will be undertaken. The work will first address this question both in C. glabrata and C. albicans. In C. glabrata, mutations in the transcription factor CgPDR1 (so called GOF mutations for gain-of-function) are participating to the upregulation of at least ABC transporters involved in azole resistance. The occurrence of the same mutations results in enhanced virulence and fit-ness in animal models. In this proposal, the transcriptome of C. glabrata in the presence of GOF mutations in CgPDR1 will be obtained in order to identify genes responsible for gain of fitness and virulence. The candidate genes will be next inactivated to challenge their role as virulence factors in animal experiments. Genes with the desired phenotypes will be further characterized and their precise role in virulence/fitness further investigated by ex-vivo assays (endocytosis by macrophage/epithelial cells and fungal replication/survival). In C. albicans, several GOF mutations in transcriptional regulators are associated with resis-tance to antifungal agents. GOF mutations in TAC1, MRR1 are involved in the upregulation of multidrug transporters while those in UPC2 participates in the upregulation of sterol biosyn-thetic genes, among which ERG11, the target of azoles. It is largely unknown whether GOF mutations in these transcriptional activators have a positive impact on the fitness and viru-lence of C. albicans in animal models. Using strains with identical genetic backgrounds, this work will attempt to resolve this still unanswered question with the same approach than above-described for C. glabrata.In conclusion, our results are expected to highlight the costs or benefits of the development of antifungal resistance for host interactions in two major fungal pathogens. Identification of ge-nes regulated by transcriptional regulator of antifungal resistance but involved in this critical balance if of interest because they might reveal key steps of fungal pathogenesis and can rep-resent potential targets of future therapy.