R. S. Al-dhaheri and L. J. Douglas, Apoptosis in Candida biofilms exposed to amphotericin B, J. Med. Microbiol, vol.59, pp.149-157, 2010.

M. Augenbraun, J. Livingston, R. Parker, S. Lederman, S. Chavoustie et al., Fluconazole and MGCD290 in vulvo vaginal candidiasis (VVC): results from a randomized phase II study, Poster 1330 in IDWeek, 2013.

K. J. Bitterman, R. M. Anderson, H. Y. Cohen, M. Latorre-esteves, and D. A. Sinclair, Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1, J. Biol. Chem, vol.277, pp.45099-45107, 2002.

G. D. Brown, D. W. Denning, N. A. Gow, S. M. Levitz, M. G. Netea et al., Hidden killers: human fungal infections, Sci. Transl. Med, vol.4, pp.165-178, 2012.

E. P. Candido, R. Reeves, D. , and J. R. , Sodium butyrate inhibits histone deacetylation in cultured cells, Cell, vol.14, pp.90305-90312, 1978.

A. A. Carmen, P. R. Griffin, J. R. Calaycay, S. E. Rundlett, Y. Suka et al., Yeast HOS3 forms a novel trichostatin A-insensitive homodimer with intrinsic histone deacetylase activity, Proc. Natl. Acad. Sci. U.S.A, vol.96, pp.12356-12361, 1999.

L. E. Cowen and S. Lindquist, Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi, Science, vol.309, pp.2185-2189, 2005.

A. De-las-peñas, J. Juárez-cepeda, E. López-fuentes, M. Briones-martín-delcampo, G. Gutiérrez-escobedo et al., Local and regional chromatin silencing in Candida glabrata: consequences for adhesion and the response to stress, FEMS Yeast Res, vol.15, p.56, 2015.

D. W. Denning and M. J. Bromley, Infectious disease. How to bolster the antifungal pipeline, Science, vol.347, pp.1414-1416, 2015.

R. Domergue, I. Castaño, A. De-las-peñas, M. Zupancic, V. Lockatell et al., Nicotinic acid limitation regulates silencing of Candida adhesins during UTI, Science, vol.308, pp.866-870, 2005.

D. Hnisz, A. F. Bardet, C. J. Nobile, A. Petryshyn, W. Glaser et al., A histone deacetylase adjusts transcription kinetics at coding sequences during Candida albicans morphogenesis, PLoS Genet, vol.8, 2012.

D. Hnisz, O. Majer, I. E. Frohner, V. Komnenovic, and K. Kuchler, , 2010.

, The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans, PLoS Pathog, vol.6, p.1000889

D. Hnisz, T. Schwarzmüller, and K. Kuchler, Transcriptional loops meet chromatin: a dual-layer network controls white-opaque switching in Candida albicans, Mol. Microbiol, vol.74, pp.1-15, 2009.

S. Kapoor, L. Zhu, C. Froyd, T. Liu, and L. N. Rusche, Regional centromeres in the yeast Candida lusitaniae lack pericentromeric heterochromatin, Proc. Natl. Acad. Sci. U.S.A, vol.112, pp.12139-12144, 2015.

G. Karthikeyan, M. Paul-satyaseela, N. Dhatchana-moorthy, R. Gopalaswamy, and S. Narayanan, Functional characterization of Candida albicans Hos2 histone deacetylase, 1000.

J. Kim, J. Lee, and J. Lee, Histone deacetylase-mediated morphological transition in Candida albicans, J. Microbiol, vol.53, pp.805-811, 2015.

T. Kim, Z. Xu, S. Clauder-münster, L. M. Steinmetz, and S. Buratowski, Set3 HDAC mediates effects of overlapping noncoding transcription on gene induction kinetics, Cell, vol.150, pp.1158-1169, 2012.

A. J. Klar, T. Srikantha, and D. R. Soll, A histone deacetylation inhibitor and mutant promote colony-type switching of the human pathogen Candida albicans, Genetics, vol.158, pp.919-924, 2001.

C. A. Kvaal, T. Srikantha, and D. R. Soll, Misexpression of the white-phasespecific gene WH11 in the opaque phase of Candida albicans affects switching and virulence, Infect. Immun, vol.65, pp.4468-4475, 1997.

J. Landry, A. Sutton, S. T. Tafrov, R. C. Heller, J. Stebbins et al., The silencing protein SIR2 and its homologs are NADdependent protein deacetylases, Proc. Natl. Acad. Sci. U.S.A, vol.97, pp.5807-5811, 2000.

J. Lee, J. Oh, M. Ku, J. Kim, J. Lee et al., Ssn6 has dual roles in Candida albicans filament development through the interaction with Rpd31, FEBS Lett, vol.589, pp.513-520, 2015.

X. Li, Q. Cai, H. Mei, X. Zhou, Y. Shen et al., The Rpd3/Hda1 family of histone deacetylases regulates azole resistance in Candida albicans, J. Antimicrob. Chemother, vol.70, 1993.

M. S. Lionakis, Drosophila and Galleria insect model hosts. Virulence, vol.2, pp.521-527, 2011.

T. T. Liu, R. E. Lee, K. S. Barker, R. E. Lee, L. Wei et al., Genome-wide expression profiling of the response to azole, polyene, echinocandin, and pyrimidine antifungal agents in Candida albicans, Antimicrob. Agents Chemother, vol.49, pp.2226-2236, 2005.

P. M. Lombardi, K. E. Cole, D. P. Dowling, and D. W. Christianson, Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes, Curr. Opin. Struct. Biol, vol.21, pp.735-743, 2011.

Y. Lu, C. Su, and H. Liu, A GATA transcription factor recruits Hda1 in response to reduced Tor1 signaling to establish a hyphal chromatin state in Candida albicans, PLoS Pathog, vol.8, p.1002663, 2012.

Y. Lu, C. Su, A. Wang, and H. Liu, Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance, PLoS Biol, vol.9, p.1001105, 2011.

D. Maglott, J. Ostell, K. D. Pruitt, and T. Tatusova, Entrez Gene: gene-centered information at NCBI, Nucleic Acids Res, vol.35, pp.26-31, 2007.

A. Mai, D. Rotili, S. Massa, G. Brosch, G. Simonetti et al., Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans, Bioorg. Med. Chem. Lett, vol.17, pp.1221-1225, 2007.

D. Maubon, C. Garnaud, T. Calandra, D. Sanglard, and M. Cornet, Resistance of Candida spp. to antifungal drugs in the ICU: where are we now?, Intensive Care Med, vol.40, pp.1241-1255, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01474519

J. Morschhäuser, Regulation of multidrug resistance in pathogenic fungi, Fungal Genet. Biol, vol.47, pp.94-106, 2010.

M. Mottamal, S. Zheng, T. L. Huang, W. , and G. , Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents, Mol. Basel Switz, vol.20, pp.3898-3941, 2015.

C. J. Nobile, E. P. Fox, N. Hartooni, K. F. Mitchell, D. Hnisz et al., A histone deacetylase complex mediates biofilm dispersal and drug resistance in Candida albicans, mBio, vol.5, pp.1201-1214, 2014.
DOI : 10.1128/mbio.01201-14
URL : https://mbio.asm.org/content/5/3/e01201-14.full.pdf

C. J. Nobile, E. P. Fox, J. E. Nett, T. R. Sorrells, Q. M. Mitrovich et al., A recently evolved transcriptional network controls biofilm development in Candida albicans, Cell, vol.148, pp.126-138, 2012.
DOI : 10.1016/j.cell.2011.10.048
URL : https://doi.org/10.1016/j.cell.2011.10.048

E. Orta-zavalza, G. Guerrero-serrano, G. Gutiérrez-escobedo, I. Cañas-villamar, J. Juárez-cepeda et al., Local silencing controls the oxidative stress response and the multidrug resistance in Candida glabrata, Mol. Microbiol, vol.88, pp.1135-1148, 2013.

J. Pérez-martín, J. A. Uría, J. , and A. D. , Phenotypic switching in Candida albicans is controlled by a SIR2 gene, EMBO J, vol.18, pp.2580-2592, 1999.

D. S. Perlin, E. Shor, and Y. Zhao, Update on antifungal drug resistance, Curr. Clin. Microbiol. Rep, vol.2, pp.84-95, 2015.
DOI : 10.1007/s40588-015-0015-1
URL : https://link.springer.com/content/pdf/10.1007%2Fs40588-015-0015-1.pdf

M. A. Pfaller, S. A. Messer, N. Georgopapadakou, L. A. Martell, J. M. Besterman et al., Activity of MGCD290, a Hos2 histone deacetylase inhibitor, in combination with azole antifungals against opportunistic fungal pathogens, J. Clin. Microbiol, vol.47, pp.3797-3804, 2009.

M. A. Pfaller, P. R. Rhomberg, S. A. Messer, and M. Castanheira, In vitro activity of a Hos2 deacetylase inhibitor, MGCD290, in combination with echinocandins against echinocandin-resistant Candida species, Diagn. Microbiol. Infect. Dis, vol.81, pp.259-263, 2015.

C. J. Phiel, F. Zhang, E. Y. Huang, M. G. Guenther, M. A. Lazar et al., Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen, J. Biol. Chem, vol.276, pp.36734-36741, 2001.

M. Polke, B. Hube, and I. D. Jacobsen, Candida survival strategies, Adv. Appl. Microbiol, vol.91, pp.139-235, 2015.

M. N. Rai, S. Balusu, N. Gorityala, L. Dandu, and R. Kaur, Functional genomic analysis of Candida glabrata-macrophage interaction: role of chromatin remodeling in virulence, PLoS Pathog, vol.8, p.1002863, 2012.

S. K. Rajasekharan, S. Ramesh, and D. Bakkiyaraj, Synergy of flavonoids with HDAC inhibitor: new approach to target Candida tropicalis biofilms, J. Chemother, vol.27, pp.246-249, 2015.

N. Robbins, M. D. Leach, and L. E. Cowen, Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance, Cell Rep, vol.2, pp.878-888, 2012.

T. Roger, J. Lugrin, D. Le-roy, G. Goy, M. Mombelli et al., Histone deacetylase inhibitors impair innate immune responses to toll-like receptor agonists and to infection, Blood, vol.117, pp.1205-1217, 2011.

S. E. Rundlett, A. A. Carmen, R. Kobayashi, S. Bavykin, B. M. Turner et al., HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription, Proc. Natl. Acad. Sci. U.S.A, vol.93, pp.14503-14508, 1996.

B. D. Sanders, K. Zhao, J. T. Slama, and R. Marmorstein, Structural basis for nicotinamide inhibition and base exchange in Sir2 enzymes, Mol. Cell, vol.25, pp.463-472, 2007.

E. Shor and D. S. Perlin, Coping with stress and the emergence of multidrug resistance in fungi, PLoS Pathog, vol.11, p.1004668, 2015.

G. Simonetti, C. Passariello, D. Rotili, A. Mai, E. Garaci et al., Histone deacetylase inhibitors may reduce pathogenicity and virulence Frontiers in Microbiology | www.frontiersin, vol.7, p.1238, 2007.

. Garnaud, Cap2-HAP complex is a critical transcriptional regulator that has dual but contrasting roles in regulation of iron homeostasis in Candida albicans, FEMS Yeast Res, vol.7, pp.25154-25170, 2011.

W. L. Smith and T. D. Edlind, Histone deacetylase inhibitors enhance Candida albicans sensitivity to azoles and related antifungals: correlation with reduction in CDR and ERG upregulation, Antimicrob. Agents Chemother, vol.46, pp.3532-3539, 2002.

J. R. Somoza, R. J. Skene, B. A. Katz, C. Mol, J. D. Ho et al., Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases, Structure, vol.12, pp.1325-1334, 2004.

T. Srikantha, L. Tsai, K. Daniels, A. J. Klar, and D. R. Soll, The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans, J. Bacteriol, vol.183, pp.4614-4625, 2001.

J. S. Stevenson and H. Liu, Regulation of white and opaque cell-type formation in Candida albicans by Rtt109 and Hst3, Mol. Microbiol, vol.81, pp.1078-1091, 2011.

J. S. Stevenson and H. Liu, Nucleosome assembly factors CAF-1 and HIR modulate epigenetic switching frequencies in an H3K56 acetylationassociated manner in Candida albicans, Eukaryot. Cell, vol.12, pp.591-603, 2013.

P. E. Sudbery, Growth of Candida albicans hyphae, Nat. Rev. Microbiol, vol.9, pp.737-748, 2011.

H. T. Taff, K. F. Mitchell, J. A. Edward, and D. R. Andes, Mechanisms of Candida biofilm drug resistance, Future Microbiol, vol.8, pp.1325-1337, 2013.

P. Trojer, E. M. Brandtner, G. Brosch, P. Loidl, J. Galehr et al., Histone deacetylases in fungi: novel members, new facts, Nucleic Acids Res, vol.31, pp.3971-3981, 2003.

M. Tscherner, F. Zwolanek, S. Jenull, F. J. Sedlazeck, A. Petryshyn et al., The Candida albicans histone acetyltransferase Hat1 regulates stress resistance and virulence via distinct chromatin assembly pathways, PLoS Pathog, vol.11, 2015.
DOI : 10.1371/journal.ppat.1005218
URL : https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005218&type=printable

N. Tsuji, M. Kobayashi, K. Nagashima, Y. Wakisaka, and K. Koizumi, A new antifungal antibiotic, trichostatin, J. Antibiot, vol.29, pp.1-6, 1976.

M. A. Uhl, M. Biery, N. Craig, J. , and A. D. , Haploinsufficiencybased large-scale forward genetic analysis of filamentous growth in the diploid human fungal pathogen C.albicans, EMBO J, vol.22, pp.2668-2678, 2003.

P. Uppuluri, C. G. Pierce, D. P. Thomas, S. S. Bubeck, S. P. Saville et al., The transcriptional regulator Nrg1p controls Candida albicans biofilm formation and dispersion, Eukaryot. Cell, vol.9, pp.1531-1537, 2010.

H. Wurtele, S. Tsao, G. Lépine, A. Mullick, J. Tremblay et al., Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy, Nat. Med, vol.16, 2010.

M. Yoshida, M. Kijima, M. Akita, and T. Beppu, Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A, J. Biol. Chem, vol.265, pp.17174-17179, 1990.

M. Yoshida, S. Nomura, and T. Beppu, Effects of trichostatins on differentiation of murine erythroleukemia cells, Cancer Res, vol.47, pp.3688-3691, 1987.

L. F. Zacchi, W. L. Schulz, and D. A. Davis, HOS2 and HDA1 encode histone deacetylases with opposing roles in Candida albicans morphogenesis, PLoS ONE, vol.5, 2010.

L. Zhang and W. Xu, Histone deacetylase inhibitors for enhancing activity of antifungal agent: a patent evaluation of WO2014041424(A1), 2015.

B. D. Alexander, M. D. Johnson, and C. D. Pfeiffer, Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations, Clin Infect Dis, vol.56, pp.1724-1756, 2013.

R. K. Shields, M. H. Nguyen, and E. G. Press, Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure, Antimicrob Agents Chemother, vol.57, pp.3528-3563, 2013.
DOI : 10.1128/aac.00136-13
URL : https://aac.asm.org/content/57/8/3528.full.pdf

T. C. White, K. A. Marr, and R. A. Bowden, Clinical, cellular, and molecular factors that contribute to antifungal drug resistance, Clin Microbiol Rev, vol.11, pp.382-402, 1998.
DOI : 10.1128/cmr.11.2.382
URL : https://cmr.asm.org/content/cmr/11/2/382.full.pdf

R. D. Cannon, E. Lamping, and A. R. Holmes, Efflux-mediated antifungal drug resistance, Clin Microbiol Rev, vol.22, pp.291-321, 2009.
DOI : 10.1128/cmr.00051-08
URL : https://cmr.asm.org/content/22/2/291.full.pdf

D. Sanglard, A. Coste, and S. Ferrari, Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation, FEMS Yeast Res, vol.9, pp.1029-50, 2009.

F. Morio, C. Loge, and B. Besse, Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature, Diagn Microbiol Infect Dis, vol.66, pp.373-84, 2010.

F. Morio, F. Pagniez, and C. Lacroix, Amino acid substitutions in the Candida albicans sterol D5,6-desaturase (Erg3p) confer azole resistance: characterization of two novel mutants with impaired virulence, J Antimicrob Chemother, vol.67, pp.1705-1721, 2012.

J. L. Rodriguez-tudela, M. C. Arendrup, and F. Barchiesi, EUCAST definitive document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts. Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST), Clin Microbiol Infect, vol.14, pp.398-405, 2008.

M. C. Arendrup, M. Cuenca-estrella, and C. Lass-flö-rl, Breakpoints for antifungal agents: an update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp, Drug Resist Updat, vol.16, pp.81-95, 2013.

M. Bougnoux, A. Tavanti, and C. Bouchier, Collaborative consensus for optimized multilocus sequence typing of Candida albicans, J Clin Microbiol, vol.41, pp.5265-5271, 2003.
DOI : 10.1128/jcm.41.11.5265-5266.2003
URL : https://jcm.asm.org/content/41/11/5265.full.pdf

R. Sabino, P. Sampaio, and L. Rosado, New polymorphic microsatellite markers able to distinguish among Candida parapsilosis sensu stricto isolates, J Clin Microbiol, vol.48, pp.1677-82, 2010.
DOI : 10.1128/jcm.02151-09
URL : https://jcm.asm.org/content/48/5/1677.full.pdf

A. Enache-angoulvant, M. Bourget, and S. Brisse, Multilocus microsatellite markers for molecular typing of Candida glabrata: application to analysis of genetic relationships between bloodstream and digestive system isolates, J Clin Microbiol, vol.48, pp.4028-4062, 2010.

S. Perea, J. L. Ló-pez-ribot, and W. R. Kirkpatrick, Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients, Antimicrob Agents Chemother, vol.45, pp.2676-84, 2001.

A. S. Chau, M. Gurnani, and R. Hawkinson, Inactivation of sterol D5,6-desaturase attenuates virulence in Candida albicans, Antimicrob Agents Chemother, vol.49, pp.3646-51, 2005.

A. Kolaczkowska, M. Kolaczkowski, and A. Delahodde, Functional dissection of Pdr1p, a regulator of multidrug resistance in Saccharomyces cerevisiae, Mol Genet Genomics, vol.267, pp.96-106, 2002.

J. Vermitsky, K. D. Earhart, and W. L. Smith, Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies, Mol Microbiol, vol.61, pp.704-726, 2006.

T. Schwarzmü-ller, B. Ma, and E. Hiller, Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes, PLoS Pathog, vol.10, p.1004211, 2014.

J. K. Thakur, H. Arthanari, and F. Yang, A nuclear receptor-like pathway regulating multidrug resistance in fungi, Nature, vol.452, pp.604-613, 2008.

S. D. Singh-babak, T. Babak, and S. Diezmann, Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata, PLoS Pathog, vol.8, p.1002718, 2012.

S. Ferrari, F. Ischer, and D. Calabrese, Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence, PLoS Pathog, vol.5, p.1000268, 2009.

G. Garcia-effron, S. Lee, and S. Park, Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of, vol.1, p.3

. Garnaud, 2564 synthase: implication for the existing susceptibility breakpoint, Antimicrob Agents Chemother, vol.53, pp.3690-3699, 2009.

E. Dannaoui, M. Desnos-ollivier, and D. Garcia-hermoso, Candida spp. with acquired echinocandin resistance, Emerg Infect Dis, vol.18, pp.86-90, 2004.
URL : https://hal.archives-ouvertes.fr/hal-00759177

M. Sanguinetti, B. Posteraro, and B. Fiori, Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance, Antimicrob Agents Chemother, vol.49, pp.668-79, 2005.

A. P. Silva, I. M. Miranda, and A. Guida, Transcriptional profiling of azoleresistant Candida parapsilosis strains, Antimicrob Agents Chemother, vol.55, pp.3546-56, 2011.

F. Chapeland-leclerc, C. Hennequin, and N. Papon, Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient, Antimicrob Agents Chemother, vol.54, pp.1360-1362, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00594730

A. T. Coste, M. Karababa, and F. Ischer, TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2, Eukaryot Cell, vol.3, pp.1639-52, 2004.

D. Sanglard, K. Kuchler, and F. Ischer, Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters, Antimicrob Agents Chemother, vol.39, pp.2378-86, 1995.

D. M. Maccallum, A. Coste, and F. Ischer, Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection, Antimicrob Agents Chemother, vol.54, pp.1476-83, 2010.

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, Les levures ont été cultivées à 30°C, en milieu YPD (yeast extract 0,5%, peptone 1% et glucose 2%) ou SC (Synthetic Complete : Yeast Nitrogen Base 0,17 %, ammonium sulfate 0,5 %, glucose 2 % et acides aminés 0,2 %), solide ou liquide. Les milieux SC-M-C (SC sans méthionine ni cystéine), SC+M+C (SC + méthionine 5mM + cystéine 0,25 mM) et SC+M+C-U (SC + méthionine 5mM + cystéine 0, p.25

, Les levures ont été cultivées en milieu SC-M-C jusqu'à, p.5

, centrifugation et re-suspendues dans de l'eau stérile de façon à obtenir une DO 600 égale à 0,13. Des dilutions successives d'un facteur 3 ont ensuite été réalisées à partir de ces suspensions calibrées, et des gouttes de volume égal ont été déposées sur milieu approprié, Les boites ont été incubées 24h à 30°C

, Brièvement, les levures ont été cultivées en milieu SC approprié jusqu'à obtention d'une DO 600

, glycérol 10% ; PMSF 0,5 mM ; cOmplete? Mini EDTA-free Protease Inhibitor Cocktail (Roche)). Les levures ont ensuite subi une lyse mécanique à l'aide de billes de zirconium de

, Le surnageant a été collecté par centrifugation (15 min, 10000 g, 4°C), puis la concentration en protéines estimées par la méthode Bradford

, Cinq à 10 µg de l'extrait de protéines totales a ensuite été déposé sur gel

M. Gel, La membrane a ensuite été incubée dans du PBS + Tween 0,1% + lait 5% pendant 45 minutes, puis en présence de l'anticorps primaire anti-ScBdf1 (1/1000) pendant une nuit. Après lavage, la membrane a alors été incubée en présence de l'anticorps secondaire anti-lapin marqué à la HRP (1/5000), .) et suivi d'une migration de 1h30 à 6h à 110V

, Après migration, le SDS-Page a été coloré par le Coomassie Bio-Safe (Biorad) pendant 90 minutes

, Afin de confirmer que RIM101 agit bien en amont de HSP90, des sites de liaison de Rim101p ont été recherchés au niveau du promoteur de HSP90. Plusieurs séquences de ce type ont été décrites : GCCAAG, CCAAGA et (G/A)CCAAGAA (203). Cependant, aucune n'a été retrouvée dans le promoteur de HSP90. Il semblerait toutefois que d'autres sites de liaison de Rim101 à l'ADN existent (203)

, Si l'implication de Hsp90 dans la tolérance aux antifongiques médiée par la voie Rim est confirmée

, L'inhibition de la voie Rim est une nouvelle stratégie antifongique d'intérêt

L. Cependant and . Développement, de cet anticorps a été arrêté suite à des problèmes de qualité inconstante et de toxicité. Hsp90 n'étant pas une protéine strictement fongique, cibler directement cette protéine expose en effet à un risque de toxicité par action sur la protéine Hsp90 humaine. A l'inverse, cibler Hsp90 par l'intermédiaire de la voie Rim permettrait de s

, D'une part, la voie Rim n'étant activée qu'en conditions neutres ou alcalines, cette stratégie ne présenterait un intérêt que pour le traitement des infections à Candida spp. touchant des sites dont le pH physiologique est neutre ou alcalin. Cela est toutefois le cas des candidémies ou des candidoses intra-abdominales, qui représentent une part importante des candidoses invasives (202). D'autre part, l'implication de la voie Rim dans la tolérance aux antifongiques n'a à ce jour été démontrée que pour C. albicans. Il serait intéressant d'étudier l'implication de la voie Rim dans la tolérance aux antifongiques pour d'autres espèces fréquemment responsables de candidoses invasives, comme C. glabrata et C. parapsilosis. Si le rôle de Hsp90 dans la tolérance aux antifongiques médiée par la voie Rim est confirmé, il est possible qu'aucun effet de la voie Rim dans la tolérance aux échinocandines ne soit mis en évidence chez C. glabrata, Quelques limites à l'association d'inhibiteurs de la voie Rim et d'antifongiques déjà disponibles en tant que nouvelle stratégie antifongique peuvent toutefois être soulevées

, La stratégie thérapeutique proposée dans les perspectives de ce travail, soit l'association d'inhibiteurs de la voie Rim aux antifongiques déjà disponibles, permettrait de s'affranchir de ce problème, la voie Rim étant spécifique du règne fongique. De plus, cette voie étant conservée au sein du règne fongique, une telle stratégie pourrait avoir un large spectre d'activité, Un des principaux freins au développement de nouvelles molécules antifongiques est la proximité entre les cellules fongiques et les cellules humaines, toutes deux eucaryotes

, Bdf1 : nouvelle cible antifongique ? Le dernier axe de ma thèse portait sur l'étude de la protéine BET fongique Bdf1 en tant que nouvelle cible antifongique. Les résultats obtenus montrent que l, vol.7

J. Bouchara, M. Pihet, L. De-gentile, B. Cimon, and D. Chabasse, Levures et levuroses, Cah Form Biol Médicale, issue.44, 2010.

J. Latgé, The cell wall: a carbohydrate armour for the fungal cell, Mol Microbiol, vol.66, issue.2, pp.279-90, 2007.

V. Aimanianda and J. Latgé, Problems and hopes in the development of drugs targeting the fungal cell wall, Expert Rev Anti Infect Ther, vol.8, issue.4, pp.359-64, 2010.

T. Y. James, F. Kauff, C. L. Schoch, P. B. Matheny, V. Hofstetter et al., Reconstructing the early evolution of Fungi using a six-gene phylogeny, Nature, vol.443, issue.7113, pp.818-840, 2006.

S. Silva, M. Negri, M. Henriques, R. Oliveira, D. W. Williams et al., Candida glabrata, Candida parapsilosis and Candida tropicalis: biology, epidemiology, pathogenicity and antifungal resistance, FEMS Microbiol Rev, vol.36, issue.2, pp.288-305, 2012.

R. J. Bennett, Coming of age--sexual reproduction in Candida species, PLoS Pathog, vol.6, issue.12, p.1001155, 2010.

G. Butler, M. D. Rasmussen, M. F. Lin, M. Santos, S. Sakthikumar et al., Evolution of pathogenicity and sexual reproduction in eight Candida genomes, Nature, vol.459, issue.7247, pp.657-62, 2009.

N. Papon, V. Courdavault, M. Clastre, and R. J. Bennett, Emerging and emerged pathogenic Candida species: beyond the Candida albicans paradigm, PLoS Pathog, vol.9, issue.9, p.1003550, 2013.
URL : https://hal.archives-ouvertes.fr/hal-01133509

M. A. Pfaller and D. J. Diekema, Epidemiology of invasive mycoses in North America, Crit Rev Microbiol, vol.36, issue.1, pp.1-53, 2010.

G. D. Brown, D. W. Denning, N. Gow, S. M. Levitz, M. G. Netea et al., Hidden killers: human fungal infections, Sci Transl Med, vol.4, issue.165, pp.165-178, 2012.

T. Jones, N. A. Federspiel, H. Chibana, J. Dungan, S. Kalman et al., The diploid genome sequence of Candida albicans, Proc Natl Acad Sci, vol.101, issue.19, pp.7329-7363, 2004.

M. S. Skrzypek, J. Binkley, G. Binkley, S. R. Miyasato, M. Simison et al., The Candida Genome Database (CGD): incorporation of Assembly 22, systematic identifiers and visualization of high throughput sequencing data, Nucleic Acids Res, vol.45, issue.D1, pp.592-598, 2017.

L. Kruglyak and D. A. Nickerson, Variation is the spice of life, Nat Genet, vol.27, issue.3, pp.234-240, 2001.

I. V. Ene and R. J. Bennett, The cryptic sexual strategies of human fungal pathogens, Nat Rev Microbiol, vol.12, issue.4, pp.239-51, 2014.

S. M. Noble, B. A. Gianetti, and J. N. Witchley, Candida albicans cell-type switching and functional plasticity in the mammalian host, Nat Rev Microbiol, vol.15, issue.2, pp.96-108, 2017.

J. M. Sheltzer, H. M. Blank, S. J. Pfau, Y. Tange, B. M. George et al., Aneuploidy drives genomic instability in yeast, Science, vol.333, issue.6045, pp.1026-1056, 2011.
DOI : 10.1126/science.1206412
URL : http://europepmc.org/articles/pmc3278960?pdf=render

P. E. Sudbery, Growth of Candida albicans hyphae, Nat Rev Microbiol, vol.9, issue.10, pp.737-785, 2011.
DOI : 10.1038/nrmicro2636

P. Sudbery, N. Gow, and J. Berman, The distinct morphogenic states of Candida albicans, Trends Microbiol, vol.12, issue.7, pp.317-341, 2004.

N. Gow, F. L. Van-de-veerdonk, A. Brown, and M. G. Netea, Candida albicans morphogenesis and host defence: discriminating invasion from colonization, Nat Rev Microbiol, vol.10, issue.2, pp.112-134, 2012.
DOI : 10.1038/nrmicro2711
URL : http://europepmc.org/articles/pmc3624162?pdf=render

J. Xie, L. Tao, C. J. Nobile, Y. Tong, G. Guan et al., White-opaque switching in natural MTLa/? isolates of Candida albicans: evolutionary implications for roles in host adaptation, pathogenesis, and sex, PLoS Biol, vol.11, issue.3, p.1001525, 2013.

E. M. Mallick, A. C. Bergeron, S. K. Jones, Z. R. Newman, K. M. Brothers et al., Phenotypic Plasticity Regulates Candida albicans Interactions and Virulence in the Vertebrate Host, Front Microbiol, vol.7, p.780, 2016.

J. Morschhäuser, Regulation of white-opaque switching in Candida albicans, Med Microbiol Immunol (Berl), vol.199, issue.3, pp.165-72, 2010.

L. Tao, H. Du, G. Guan, Y. Dai, C. J. Nobile et al., Discovery of a "white-gray-opaque" tristable phenotypic switching system in Candida albicans: roles of non-genetic diversity in host adaptation, PLoS Biol, vol.12, issue.4, p.1001830, 2014.

K. Pande, C. Chen, and S. M. Noble, Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism, Nat Genet, vol.45, issue.9, pp.1088-91, 2013.

N. Gow, A developmental program for Candida commensalism, Nat Genet, vol.45, issue.9, pp.967-975, 2013.

M. H. Al-yasiri, N. , L. &apos;ollivier, C. Lachaud, L. Bourgeois et al., Opportunistic fungal pathogen Candida glabrata circulates between humans and yellow-legged gulls. Sci Rep, vol.6, p.36157, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01455795

C. Lass-flörl, The changing face of epidemiology of invasive fungal disease in Europe, Mycoses, vol.52, issue.3, pp.197-205, 2009.

M. C. Arendrup, Epidemiology of invasive candidiasis, Curr Opin Crit Care, vol.16, issue.5, pp.445-52, 2010.

A. M. Borman, R. Petch, C. J. Linton, M. D. Palmer, P. D. Bridge et al., Candida nivariensis, an emerging pathogenic fungus with multidrug resistance to antifungal agents, J Clin Microbiol, vol.46, issue.3, pp.933-941, 2008.

A. Glöckner and O. A. Cornely, Candida glabrata: unique features and challenges in the clinical management of invasive infections, Mycoses, vol.58, issue.8, pp.445-50, 2015.

S. Wong, M. A. Fares, W. Zimmermann, G. Butler, and K. H. Wolfe, Evidence from comparative genomics for a complete sexual cycle in the "asexual" pathogenic yeast Candida glabrata, Genome Biol, vol.4, issue.2, p.10, 2003.

T. Gabaldón, T. Martin, M. Marcet-houben, P. Durrens, M. Bolotin-fukuhara et al., Comparative genomics of emerging pathogens in the Candida glabrata clade, BMC Genomics, vol.14, p.623, 2013.

J. Linde, S. Duggan, M. Weber, F. Horn, P. Sieber et al., Defining the transcriptomic landscape of Candida glabrata by RNA-Seq, Nucleic Acids Res, vol.43, issue.3, pp.1392-406, 2015.

T. Gabaldón, M. A. Naranjo-ortíz, and M. Marcet-houben, Evolutionary genomics of yeast pathogens in the Saccharomycotina, FEMS Yeast Res, vol.16, issue.6, 2016.

C. Csank and K. Haynes, Candida glabrata displays pseudohyphal growth, FEMS Microbiol Lett, vol.189, issue.1, pp.115-135, 2000.

S. Brunke, K. Seider, D. Fischer, I. D. Jacobsen, L. Kasper et al., One small step for a yeast--microevolution within macrophages renders Candida glabrata hypervirulent due to a single point mutation, PLoS Pathog, vol.10, issue.10, p.1004478, 2014.
URL : https://hal.archives-ouvertes.fr/pasteur-01518441

M. S. Lionakis and M. G. Netea, Candida and host determinants of susceptibility to invasive candidiasis, PLoS Pathog, vol.9, issue.1, p.1003079, 2013.

N. Gow and B. Hube, Importance of the Candida albicans cell wall during commensalism and infection, Curr Opin Microbiol, vol.15, issue.4, pp.406-418, 2012.

M. Polke, B. Hube, and I. D. Jacobsen, Candida survival strategies, Adv Appl Microbiol, vol.91, pp.139-235, 2015.

F. L. Mayer, D. Wilson, and B. Hube, Hsp21 Potentiates Antifungal Drug Tolerance in Candida albicans, PLoS ONE, vol.8, issue.3, 2013.

D. Toubas, Epidémiologie des candidoses invasives, Rev Fr Lab, issue.450, pp.27-36, 2013.

S. R. Lockhart, K. A. Etienne, S. Vallabhaneni, J. Farooqi, A. Chowdhary et al., Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses, Clin Infect Dis Off Publ Infect Dis Soc Am, 2016.

P. Eggimann, J. Garbino, and D. Pittet, Epidemiology of Candida species infections in critically ill nonimmunosuppressed patients, Lancet Infect Dis, vol.3, issue.11, pp.685-702, 2003.

S. Strollo, M. S. Lionakis, J. Adjemian, C. A. Steiner, and D. R. Prevots, Epidemiology of Hospitalizations Associated with Invasive Candidiasis, vol.23, pp.7-13, 2016.

A. A. Cleveland, L. H. Harrison, M. M. Farley, R. Hollick, B. Stein et al., Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, PloS One, vol.10, issue.3, p.120452, 2008.

B. J. Kullberg and M. C. Arendrup, Invasive Candidiasis, N Engl J Med, vol.373, issue.15, pp.1445-56, 2015.

D. Bitar, O. Lortholary, F. Dromer, B. Coignard, and C. D. , Bulletin épidémiologique hebdomadaire -BEH

J. Gangneux, M. Bougnoux, C. Hennequin, C. Godet, J. Chandenier et al., An estimation of burden of serious fungal infections in France, J Mycol Medicale, vol.26, issue.4, pp.385-90, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01467554

D. Diekema, S. Arbefeville, L. Boyken, J. Kroeger, and M. Pfaller, The changing epidemiology of healthcare-associated candidemia over three decades, Diagn Microbiol Infect Dis, vol.73, issue.1, pp.45-53, 2012.

H. Wisplinghoff, T. Bischoff, S. M. Tallent, H. Seifert, R. P. Wenzel et al., Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.39, issue.3, pp.309-326, 2004.

M. A. Pfaller, G. J. Moet, S. A. Messer, R. N. Jones, and M. Castanheira, Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program, J Clin Microbiol, vol.49, issue.1, pp.396-405, 2008.

D. H. Kett, E. Azoulay, P. M. Echeverria, and J. Vincent, Extended Prevalence of Infection in ICU Study (EPIC II) Group of Investigators. Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study, Crit Care Med, vol.39, issue.4, pp.665-70, 2011.

M. A. Pfaller, M. Castanheira, S. A. Messer, G. J. Moet, and R. N. Jones, Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program, Diagn Microbiol Infect Dis, vol.68, issue.3, pp.278-83, 2008.

C. Moran, C. A. Grussemeyer, J. R. Spalding, D. K. Benjamin, and S. D. Reed, Candida albicans and nonalbicans bloodstream infections in adult and pediatric patients: comparison of mortality and costs, Pediatr Infect Dis J, vol.28, issue.5, pp.433-438, 2009.

A. Tragiannidis, C. Tsoulas, K. Kerl, and A. H. Groll, Invasive candidiasis: update on current pharmacotherapy options and future perspectives, Expert Opin Pharmacother, vol.14, issue.11, pp.1515-1543, 2013.

D. Marriott, E. G. Playford, S. Chen, M. Slavin, Q. Nguyen et al., Determinants of mortality in non-neutropenic ICU patients with candidaemia, Crit Care Lond Engl, vol.13, issue.4, p.115, 2009.

O. Leroy, J. Gangneux, P. Montravers, J. Mira, F. Gouin et al., Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France, Crit Care Med, vol.37, issue.5, pp.1612-1620, 2005.
URL : https://hal.archives-ouvertes.fr/hal-00676899

M. C. Arendrup, S. Sulim, A. Holm, L. Nielsen, S. D. Nielsen et al., Diagnostic issues, clinical characteristics, and outcomes for patients with fungemia, J Clin Microbiol, vol.49, issue.9, pp.3300-3308, 2011.

M. Bougnoux, G. Kac, P. Aegerter, C. Enfert, and J. Fagon, CandiRea Study Group. Candidemia and candiduria in critically ill patients admitted to intensive care units in France: incidence, molecular diversity, management and outcome, Intensive Care Med, vol.34, issue.2, pp.292-301, 2008.

C. C. Blyth, S. Chen, M. A. Slavin, C. Serena, Q. Nguyen et al., Not just little adults: candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric patients, Pediatrics, vol.123, issue.5, pp.1360-1368, 2009.

A. Holley, J. Dulhunty, S. Blot, J. Lipman, S. Lobo et al., Temporal trends, risk factors and outcomes in albicans and non-albicans candidaemia: an international epidemiological study in four multidisciplinary intensive care units, Int J Antimicrob Agents, vol.33, issue.6, pp.554-555, 2009.

B. Moriyama, L. A. Gordon, M. Mccarthy, S. A. Henning, T. J. Walsh et al., Emerging drugs and vaccines for candidemia, Mycoses, vol.57, issue.12, pp.718-751, 2014.

L. Ostrosky-zeichner, A. Casadevall, J. N. Galgiani, F. C. Odds, and J. H. Rex, An insight into the antifungal pipeline: selected new molecules and beyond, Nat Rev Drug Discov, vol.9, issue.9, pp.719-746, 2010.

P. Vandeputte, S. Ferrari, and A. T. Coste, Antifungal resistance and new strategies to control fungal infections, Int J Microbiol, vol.2012, p.713687, 2012.

F. C. Odds, A. Brown, and N. Gow, Antifungal agents: mechanisms of action, Trends Microbiol, vol.11, issue.6, pp.272-281, 2003.

M. A. Pfaller, S. A. Messer, P. R. Rhomberg, R. N. Jones, and M. Castanheira, In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds, J Clin Microbiol, vol.51, issue.8, pp.2608-2624, 2013.

M. A. Pfaller, P. R. Rhomberg, S. A. Messer, R. N. Jones, and M. Castanheira, Isavuconazole, micafungin, and 8 comparator antifungal agents' susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values, Diagn Microbiol Infect Dis, vol.82, issue.4, pp.303-316, 2015.

F. M. Marty, L. Ostrosky-zeichner, O. A. Cornely, K. M. Mullane, J. R. Perfect et al., Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis, Lancet Infect Dis, vol.16, issue.7, pp.828-865, 2016.

J. A. Maertens, I. I. Raad, K. A. Marr, T. F. Patterson, D. P. Kontoyiannis et al., Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial, Lancet Lond Engl, vol.387, pp.760-769, 2016.

D. Sanglard, A. Coste, and S. Ferrari, Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation, FEMS Yeast Res, vol.9, issue.7, pp.1029-50, 2009.

C. M. Hull, O. Bader, J. E. Parker, M. Weig, U. Gross et al., Two clinical isolates of Candida glabrata exhibiting reduced sensitivity to amphotericin B both harbor mutations in ERG2, Antimicrob Agents Chemother, vol.56, issue.12, pp.6417-6438, 2012.

D. S. Perlin, Current perspectives on echinocandin class drugs. Future Microbiol, vol.6, pp.441-57, 2011.

S. K. Katiyar, A. Alastruey-izquierdo, K. R. Healey, M. E. Johnson, D. S. Perlin et al., Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: implications for echinocandin resistance, Antimicrob Agents Chemother, vol.56, issue.12, pp.6304-6313, 2012.

L. A. Walker, N. Gow, and C. A. Munro, Elevated chitin content reduces the susceptibility of Candida species to caspofungin, Antimicrob Agents Chemother, vol.57, issue.1, pp.146-54, 2013.

T. M. Anderson, M. C. Clay, A. G. Cioffi, K. A. Diaz, G. S. Hisao et al., Amphotericin forms an extramembranous and fungicidal sterol sponge, Nat Chem Biol, vol.10, issue.5, pp.400-406, 2014.

B. P. Guery, M. C. Arendrup, G. Auzinger, E. Azoulay, M. Borges-sá et al., Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment. Intensive Care Med, vol.35, pp.206-220, 2009.

P. Eggimann, J. Bille, and O. Marchetti, Diagnosis of invasive candidiasis in the ICU. Ann Intensive Care, vol.1, p.37, 2011.

D. Maubon, C. Garnaud, C. T. Sanglard, D. Cornet, and M. , Resistance of Candida spp. to antifungal drugs in the ICU: where are we now? Intensive Care Med, vol.40, pp.1241-55, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01474508

P. D. Ziakas, I. S. Kourbeti, and E. Mylonakis, Systemic antifungal prophylaxis after hematopoietic stem cell transplantation: a meta-analysis, Clin Ther, vol.36, issue.2, pp.292-306, 2014.

S. Xu, J. Shen, X. Tang, B. Feng, and H. Xu, Newer antifungal agents micafungin and voriconazole for fungal infection prevention during hematopoietic cell transplantation: a metaanalysis, Eur Rev Med Pharmacol Sci, vol.20, issue.2, pp.381-90, 2016.

J. Timsit, E. Azoulay, C. Schwebel, P. E. Charles, M. Cornet et al., Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial, JAMA, vol.316, issue.15, pp.1555-64, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01405822

O. A. Cornely, M. Bassetti, C. T. Garbino, J. Kullberg, B. J. Lortholary et al., ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients, Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis, vol.18, pp.19-37, 2012.

A. J. Ullmann, M. Akova, R. Herbrecht, C. Viscoli, M. C. Arendrup et al., ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT), Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis, vol.18, pp.53-67, 2012.

P. G. Pappas, C. A. Kauffman, D. R. Andes, C. J. Clancy, K. A. Marr et al., Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.62, issue.4, pp.1-50, 2016.

D. Ellis, Amphotericin B: spectrum and resistance, J Antimicrob Chemother, vol.49, issue.1, pp.7-10, 2002.

P. G. Pappas, C. A. Kauffman, D. Andes, D. K. Benjamin, T. F. Calandra et al., Clinical Practice Guidelines for the Management Candidiasis: 2009 Update by the Infectious Diseases Society of America, Clin Infect Dis, vol.48, issue.5, pp.503-538, 2009.

E. Delarze and D. Sanglard, Defining the frontiers between antifungal resistance, tolerance and the concept of persistence, Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother, vol.23, pp.12-21, 2015.

A. Coste, A. Selmecki, A. Forche, D. Diogo, M. Bougnoux et al., Genotypic Evolution of Azole Resistance Mechanisms in Sequential Candida albicans Isolates. Eukaryot Cell, vol.6, pp.1889-904, 2007.

A. Coste, V. Turner, F. Ischer, J. Morschhäuser, A. Forche et al., A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans, Genetics, vol.172, issue.4, pp.2139-56, 2006.

R. Torelli, B. Posteraro, S. Ferrari, L. Sorda, M. Fadda et al., The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata, Mol Microbiol, vol.68, issue.1, pp.186-201, 2008.

S. Ferrari, F. Ischer, D. Calabrese, B. Posteraro, M. Sanguinetti et al., Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence, PLoS Pathog, vol.5, issue.1, p.1000268, 2009.

A. T. Coste, M. Karababa, F. Ischer, J. Bille, and D. Sanglard, TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2, Eukaryot Cell, vol.3, issue.6, pp.1639-52, 2004.

A. Lohberger, A. T. Coste, and D. Sanglard, Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1, MRR1, and UPC2 in Virulence, Eukaryot Cell, vol.13, issue.1, p.127, 2014.

Y. Wang, J. Liu, C. Shi, W. Li, Y. Zhao et al., Mutations in transcription factor Mrr2p contribute to fluconazole resistance in clinical isolates of Candida albicans, Int J Antimicrob Agents, vol.46, issue.5, pp.552-561, 2015.

J. K. Thakur, H. Arthanari, F. Yang, S. Pan, F. X. Breger et al., A nuclear receptor-like pathway regulating multidrug resistance in fungi, Nature, vol.452, issue.7187, pp.604-613, 2008.

S. Borah, R. Shivarathri, V. K. Srivastava, S. Ferrari, D. Sanglard et al., Pivotal role for a tail subunit of the RNA polymerase II mediator complex CgMed2 in azole tolerance and adherence in Candida glabrata, Antimicrob Agents Chemother, vol.58, issue.10, pp.5976-86, 2014.

J. L. Nishikawa, A. Boeszoermenyi, L. A. Vale-silva, R. Torelli, B. Posteraro et al., Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction, Nature, vol.530, issue.7591, pp.485-494, 2016.

D. Sanglard and A. T. Coste, Activity of Isavuconazole and Other Azoles against Candida Clinical Isolates and Yeast Model Systems with Known Azole Resistance Mechanisms, Antimicrob Agents Chemother, vol.60, issue.1, pp.229-267, 2015.

S. Cheng, C. J. Clancy, K. T. Nguyen, W. Clapp, and M. H. Nguyen, A Candida albicans petite mutant strain with uncoupled oxidative phosphorylation overexpresses MDR1 and has diminished susceptibility to fluconazole and voriconazole, Antimicrob Agents Chemother, vol.51, issue.5, pp.1855-1863, 2007.

J. Eddouzi, J. E. Parker, L. A. Vale-silva, A. Coste, F. Ischer et al., Molecular mechanisms of drug resistance in clinical Candida species isolated from Tunisian hospitals, Antimicrob Agents Chemother, vol.57, issue.7, pp.3182-93, 2013.

F. Morio, C. Loge, B. Besse, C. Hennequin, L. Pape et al., Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature, Diagn Microbiol Infect Dis, vol.66, issue.4, pp.373-84, 2010.

P. Marichal, L. Koymans, S. Willemsens, D. Bellens, P. Verhasselt et al., Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiol Read Engl, vol.145, pp.2701-2714, 1999.

M. Nabili, A. Gohar, A. Badali, H. Mohammadi, R. Moazeni et al., Amino acid substitutions in Erg11p of azole-resistant Candida glabrata: Possible effective substitutions and homology modelling, J Glob Antimicrob Resist, vol.5, pp.42-48, 2016.

N. Berila, S. Borecka, V. Dzugasova, J. Bojnansky, and J. Subik, Mutations in the CgPDR1 and CgERG11 genes in azole-resistant Candida glabrata clinical isolates from Slovakia, Int J Antimicrob Agents, vol.33, issue.6, pp.574-582, 2009.

S. A. Flowers, K. S. Barker, E. L. Berkow, G. Toner, S. G. Chadwick et al., Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans, Eukaryot Cell, vol.11, issue.10, pp.1289-99, 2012.

D. Sanglard and F. C. Odds, Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences, Lancet Infect Dis, vol.2, issue.2, pp.73-85, 2002.

M. Nagi, H. Nakayama, K. Tanabe, M. Bard, T. Aoyama et al., Transcription factors CgUPC2A and CgUPC2B regulate ergosterol biosynthetic genes in Candida glabrata, Genes Cells Devoted Mol Cell Mech, vol.16, issue.1, pp.80-89, 2011.

S. G. Whaley, K. E. Caudle, J. Vermitsky, S. G. Chadwick, G. Toner et al., UPC2A is required for high-level azole antifungal resistance in Candida glabrata, Antimicrob Agents Chemother, vol.58, issue.8, pp.4543-54, 2014.

F. Morio, F. Pagniez, C. Lacroix, M. Miegeville, L. Pape et al., Amino acid substitutions in the Candida albicans sterol ?5,6-desaturase (Erg3p) confer azole resistance: characterization of two novel mutants with impaired virulence, J Antimicrob Chemother, vol.67, issue.9, pp.2131-2139, 2012.

C. B. Ford, J. M. Funt, A. D. Issi, L. Guiducci, C. Martinez et al., The evolution of drug resistance in clinical isolates of Candida albicans. eLife, vol.4, p.662, 2015.

S. Poláková, C. Blume, J. A. Zárate, M. Mentel, D. Jørck-ramberg et al., Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata, Proc Natl Acad Sci, vol.106, issue.8, pp.2688-93, 2009.

K. R. Healey, Y. Zhao, W. B. Perez, S. R. Lockhart, J. D. Sobel et al., Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance, Nat Commun, vol.7, p.11128, 2016.

S. Dellière, K. Healey, M. Gits-muselli, B. Carrara, A. Barbaro et al., Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance, Front Microbiol, vol.7, p.2038, 2016.

D. Sanglard, F. Ischer, and J. Bille, Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata, Antimicrob Agents Chemother, vol.45, issue.4, pp.1174-83, 2001.

H. Tsai, A. A. Krol, K. E. Sarti, and J. E. Bennett, Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants, Antimicrob Agents Chemother, vol.50, issue.4, pp.1384-92, 2006.

S. Ferrari, M. Sanguinetti, D. Bernardis, F. Torelli, R. Posteraro et al., Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob Agents Chemother, vol.55, issue.5, pp.1852-60, 2011.
URL : https://hal.archives-ouvertes.fr/hal-01389297

S. Brun, F. Dalle, P. Saulnier, G. Renier, A. Bonnin et al., Biological consequences of petite mutations in Candida glabrata, J Antimicrob Chemother, vol.56, issue.2, pp.307-321, 2005.

L. A. Walker, N. Gow, and C. A. Munro, Fungal echinocandin resistance, Fungal Genet Biol FG B, vol.47, issue.2, pp.117-143, 2010.

D. S. Perlin, Echinocandin Resistance in Candida, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.61, issue.6, p.612, 2015.

C. A. Munro, Fungal echinocandin resistance, F1000 Biol Rep, vol.2, p.66, 2010.

G. Garcia-effron, S. Lee, S. Park, J. D. Cleary, and D. S. Perlin, Effect of Candida glabrata FKS1 and FKS2 Mutations on Echinocandin Sensitivity and Kinetics of 1,3-?-d-Glucan Synthase: Implication for the Existing Susceptibility Breakpoint, Antimicrob Agents Chemother, vol.53, issue.9, pp.3690-3699, 2009.

S. D. Singh-babak, T. Babak, S. Diezmann, J. A. Hill, J. L. Xie et al., Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata, PLoS Pathog, vol.8, issue.5, p.1002718, 2012.

J. Turnidge, G. Kahlmeter, and G. Kronvall, Statistical characterisation of bacterial wild-type MIC value distributions and the determination of epidemiological cut-off values, Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis, vol.12, issue.5, pp.418-443, 2006.

M. A. Pfaller, D. J. Diekema, D. Andes, M. C. Arendrup, S. D. Brown et al., Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria, Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother, vol.14, issue.3, pp.164-76, 2011.

J. Turnidge and D. L. Paterson, Setting and revising antibacterial susceptibility breakpoints, Clin Microbiol Rev, vol.20, issue.3, pp.391-408, 2007.

M. A. Pfaller, Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment, Am J Med, vol.125, issue.1, pp.3-13, 2012.

M. A. Pfaller and D. J. Diekema, Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, J Clin Microbiol, vol.50, issue.9, pp.2846-56, 2010.

B. D. Alexander, M. D. Johnson, C. D. Pfeiffer, C. Jiménez-ortigosa, J. Catania et al., Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.56, issue.12, pp.1724-1756, 2013.

R. K. Shields, M. H. Nguyen, E. G. Press, C. L. Updike, and C. J. Clancy, Caspofungin MICs Correlate with Treatment Outcomes among Patients with Candida glabrata Invasive Candidiasis and Prior Echinocandin Exposure, Antimicrob Agents Chemother, vol.57, issue.8, pp.3528-3563, 2013.

M. A. Pfaller, D. J. Diekema, M. A. Ghannoum, J. H. Rex, B. D. Alexander et al., Wild-type MIC distribution and epidemiological cutoff values for Aspergillus fumigatus and three triazoles as determined by the Clinical and Laboratory Standards Institute broth microdilution methods, J Clin Microbiol, vol.47, issue.10, pp.3142-3148, 2009.

M. C. Arendrup and M. A. Pfaller, Danish Fungaemia Study Group. Caspofungin Etest susceptibility testing of Candida species: risk of misclassification of susceptible isolates of C. glabrata and C. krusei when adopting the revised CLSI caspofungin breakpoints, Antimicrob Agents Chemother, vol.56, issue.7, pp.3965-3973, 2012.

R. K. Shields, M. H. Nguyen, E. G. Press, A. L. Kwa, S. Cheng et al., The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata, Antimicrob Agents Chemother, vol.56, issue.9, pp.4862-4871, 2012.

S. Bailly, D. Maubon, P. Fournier, H. Pelloux, C. Schwebel et al., Impact of antifungal prescription on relative distribution and susceptibility of Candida spp. -Trends over 10 years, J Infect, vol.72, issue.1, pp.103-114, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01470816

A. Fekkar, E. Dannaoui, I. Meyer, S. Imbert, J. Y. Brossas et al., Emergence of echinocandin-resistant Candida spp. in a hospital setting: a consequence of 10 years of increasing use of antifungal therapy?, Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol, vol.33, issue.9, pp.1489-96, 2014.

S. Vallabhaneni, A. A. Cleveland, M. M. Farley, L. H. Harrison, W. Schaffner et al., Epidemiology and Risk Factors for Echinocandin Nonsusceptible Candida glabrata Bloodstream Infections: Data From a Large Multisite Population-Based Candidemia Surveillance Program, Open Forum Infect Dis, vol.2, issue.4, p.163, 2008.

R. K. Shields, M. H. Nguyen, and C. J. Clancy, Clinical perspectives on echinocandin resistance among Candida species, Curr Opin Infect Dis, vol.28, issue.6, pp.514-536, 2015.

M. T. Montagna, G. Caggiano, G. Lovero, D. Giglio, O. Coretti et al., Epidemiology of invasive fungal infections in the intensive care unit: results of a multicenter Italian survey (AURORA Project), Infection, vol.41, issue.3, pp.645-53, 2013.

M. Castanheira, S. A. Messer, P. R. Rhomberg, and M. A. Pfaller, Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program, Diagn Microbiol Infect Dis, vol.85, issue.2, pp.200-204, 2013.

F. Chapeland-leclerc, C. Hennequin, N. Papon, T. Noël, A. Girard et al., Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient, Antimicrob Agents Chemother, vol.54, issue.3, pp.1360-1362, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00594730

M. A. Pfaller, M. Castanheira, S. R. Lockhart, A. M. Ahlquist, S. A. Messer et al., Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata, J Clin Microbiol, vol.50, issue.4, pp.1199-203, 2012.

A. A. Cleveland, M. M. Farley, L. H. Harrison, B. Stein, R. Hollick et al., Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, vol.55, pp.1352-61, 2008.

M. A. Pfaller, G. J. Moet, S. A. Messer, R. N. Jones, and M. Castanheira, Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, Antimicrob Agents Chemother, vol.55, issue.2, pp.561-567, 2008.

M. A. Pfaller, M. Castanheira, S. R. Lockhart, A. M. Ahlquist, S. A. Messer et al., Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata, J Clin Microbiol, vol.50, issue.4, pp.1199-203, 2012.

C. Renaudat, K. Sitbon, M. Desnos-ollivier, A. Fontanet, S. Bretagne et al., Candidémies en Île-de-France : données de l'Observatoire des levures, Avril, pp.12-13, 2002.

M. Baixench, N. Aoun, M. Desnos-ollivier, D. Garcia-hermoso, S. Bretagne et al., Acquired resistance to echinocandins in Candida albicans: case report and review, J Antimicrob Chemother, vol.59, issue.6, pp.1076-83, 2007.

. Invs, Dernières données et tendances sur la résistance aux anti-infectieux -Candida spp, 2013.

W. Liu, J. Tan, J. Sun, Z. Xu, M. Li et al., Invasive candidiasis in intensive care units in China: in vitro antifungal susceptibility in the China-SCAN study, J Antimicrob Chemother, vol.69, issue.1, pp.162-169, 2014.

W. J. Steinbach, F. Lamoth, and P. R. Juvvadi, Potential Microbiological Effects of Higher Dosing of Echinocandins, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.61, issue.6, pp.669-677, 2015.

K. K. Lee, D. M. Maccallum, M. D. Jacobsen, L. A. Walker, F. C. Odds et al., Elevated cell wall chitin in Candida albicans confers echinocandin resistance in vivo, Antimicrob Agents Chemother, vol.56, issue.1, pp.208-225, 2012.

C. A. Munro, Chitin and glucan, the yin and yang of the fungal cell wall, implications for antifungal drug discovery and therapy, Adv Appl Microbiol, vol.83, pp.145-72, 2013.

C. Rueda, M. Puig-asensio, J. Guinea, B. Almirante, M. Cuenca-estrella et al., Evaluation of the possible influence of trailing and paradoxical effects on the clinical outcome of patients with candidemia, Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis, vol.23, issue.1, pp.49-50, 2017.

R. S. Shapiro, N. Robbins, and L. E. Cowen, Regulatory circuitry governing fungal development, drug resistance, and disease, Microbiol Mol Biol Rev MMBR, vol.75, issue.2, pp.213-67, 2011.

D. Sanglard, F. Ischer, O. Marchetti, J. Entenza, and J. Bille, Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence, Mol Microbiol, vol.48, issue.4, pp.959-76, 2003.

S. D. Singh, N. Robbins, A. K. Zaas, W. A. Schell, J. R. Perfect et al., Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin, PLoS Pathog, vol.5, issue.7, p.1000532, 2009.

S. Yu, Y. Chang, and Y. Chen, Calcineurin signaling: lessons from Candida species, FEMS Yeast Res, vol.15, issue.4, p.16, 2015.

C. Onyewu, J. R. Blankenship, D. Poeta, M. Heitman, and J. , Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei, Antimicrob Agents Chemother, vol.47, issue.3, pp.956-64, 2003.

M. C. Cruz, A. L. Goldstein, J. R. Blankenship, D. Poeta, M. Davis et al., Calcineurin is essential for survival during membrane stress in Candida albicans, EMBO J, vol.21, issue.4, pp.546-59, 2002.

Y. Chen, J. H. Konieczka, D. J. Springer, S. E. Bowen, J. Zhang et al., Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata. G3 Bethesda Md, vol.2, pp.675-91, 2012.

L. E. Cowen, The fungal Achilles' heel: targeting Hsp90 to cripple fungal pathogens, Curr Opin Microbiol, vol.16, issue.4, pp.377-84, 2013.

X. Li, N. Robbins, T. R. O&apos;meara, and L. E. Cowen, Extensive functional redundancy in the regulation of Candida albicans drug resistance and morphogenesis by lysine deacetylases Hos2, Hda1, Rpd3 and Rpd31, Mol Microbiol, 2016.

S. L. Lafayette, C. Collins, A. K. Zaas, W. A. Schell, M. Betancourt-quiroz et al., PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90, PLoS Pathog, vol.6, issue.8, p.1001069, 2010.

S. Diezmann, M. Michaut, R. S. Shapiro, G. D. Bader, and L. E. Cowen, Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry, PLoS Genet, vol.8, issue.3, p.1002562, 2012.

T. R. O&apos;meara, A. O. Veri, E. J. Polvi, X. Li, S. F. Valaei et al., Mapping the Hsp90 Genetic Network Reveals Ergosterol Biosynthesis and Phosphatidylinositol-4-Kinase Signaling as Core Circuitry Governing Cellular Stress, PLoS Genet, vol.12, issue.6, p.1006142, 2016.

T. Miyazaki, T. Inamine, S. Yamauchi, Y. Nagayoshi, T. Saijo et al., Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata, FEMS Yeast Res, vol.10, issue.3, pp.343-52, 2010.

Y. Nagayoshi, T. Miyazaki, A. Minematsu, S. Yamauchi, T. Takazono et al., Contribution of the Slt2-regulated transcription factors to echinocandin tolerance in Candida glabrata, FEMS Yeast Res, vol.14, issue.7, pp.1128-1159, 2014.

L. Popolo, T. Gualtieri, and E. Ragni, The yeast cell-wall salvage pathway, Med Mycol, vol.39, issue.1, pp.111-132, 2001.

K. Dichtl, S. Samantaray, and J. Wagener, Cell wall integrity signalling in human pathogenic fungi, Cell Microbiol, vol.18, issue.9, pp.1228-1266, 2016.

C. J. Heilmann, A. G. Sorgo, S. Mohammadi, G. J. Sosinska, C. G. De-koster et al., Surface stress induces a conserved cell wall stress response in the pathogenic fungus Candida albicans, Eukaryot Cell, vol.12, issue.2, pp.254-64, 2013.

S. Borah, R. Shivarathri, and R. Kaur, The Rho1 GTPase-activating protein CgBem2 is required for survival of azole stress in Candida glabrata, J Biol Chem, vol.286, issue.39, pp.34311-34335, 2011.

N. P. Wiederhold, D. P. Kontoyiannis, R. A. Prince, and R. E. Lewis, Attenuation of the activity of caspofungin at high concentrations against candida albicans: possible role of cell wall integrity and calcineurin pathways, Antimicrob Agents Chemother, vol.49, issue.12, pp.5146-5154, 2005.

J. M. Cota, J. L. Grabinski, R. L. Talbert, D. S. Burgess, P. D. Rogers et al., Increases in SLT2 Expression and Chitin Content Are Associated with Incomplete Killing of Candida glabrata by Caspofungin, Antimicrob Agents Chemother, vol.52, issue.3, pp.1144-1150, 2008.

R. Diez-orejas, G. Molero, F. Navarro-garcía, J. Pla, C. Nombela et al., Reduced virulence of Candida albicans MKC1 mutants: a role for mitogen-activated protein kinase in pathogenesis, Infect Immun, vol.65, issue.2, pp.833-840, 1997.

S. E. Beese-sims, S. Pan, J. Lee, E. Hwang-wong, B. P. Cormack et al., Mutants in the Candida glabrata glycerol channels are sensitized to cell wall stress, Eukaryot Cell, vol.11, issue.12, pp.1512-1521, 2012.

J. M. Rauceo, J. R. Blankenship, S. Fanning, J. J. Hamaker, J. Deneault et al., Regulation of the Candida albicans cell wall damage response by transcription factor Sko1 and PAS kinase Psk1, Mol Biol Cell, vol.19, issue.7, pp.2741-51, 2008.

C. A. Munro, S. Selvaggini, I. De-bruijn, L. Walker, M. D. Lenardon et al., The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans, Mol Microbiol, vol.63, issue.5, pp.1399-413, 2007.

T. Schwarzmüller, B. Ma, E. Hiller, F. Istel, M. Tscherner et al., Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes, PLoS Pathog. 2014 juin, vol.10, issue.6, p.1004211

T. Prasad, P. Saini, N. A. Gaur, R. A. Vishwakarma, L. A. Khan et al., Functional Analysis of CaIPT1, a Sphingolipid Biosynthetic Gene Involved in Multidrug Resistance and Morphogenesis of Candida albicans, Antimicrob Agents Chemother, vol.49, issue.8, p.3442, 2005.

K. R. Healey, K. K. Challa, T. D. Edlind, and S. K. Katiyar, Sphingolipids mediate differential echinocandin susceptibility in Candida albicans and Aspergillus nidulans, Antimicrob Agents Chemother, vol.59, issue.6, pp.3377-84, 2015.

K. R. Healey, S. K. Katiyar, S. Raj, and T. D. Edlind, CRS-MIS in Candida glabrata: sphingolipids modulate echinocandin-Fks interaction, Mol Microbiol, vol.86, issue.2, pp.303-316, 2012.

M. Tscherner, F. Zwolanek, S. Jenull, F. J. Sedlazeck, A. Petryshyn et al., The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways, PLoS Pathog, issue.10, p.11, 2015.

H. Wurtele, S. Tsao, G. Lépine, A. Mullick, J. Tremblay et al., Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy, Nat Med, vol.16, issue.7, pp.774-80, 2010.

A. Sellam, C. Askew, E. Epp, H. Lavoie, M. Whiteway et al., Genome-wide mapping of the coactivator Ada2p yields insight into the functional roles of SAGA/ADA complex in Candida albicans, Mol Biol Cell, vol.20, issue.9, pp.2389-400, 2009.

X. Li, Q. Cai, H. Mei, X. Zhou, Y. Shen et al., The Rpd3/Hda1 family of histone deacetylases regulates azole resistance in Candida albicans, J Antimicrob Chemother, 2015.

N. Robbins, M. D. Leach, and L. E. Cowen, Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance. Cell Rep, vol.2, pp.878-88, 2012.

M. A. Pfaller, P. R. Rhomberg, S. A. Messer, and M. Castanheira, In vitro activity of a Hos2 deacetylase inhibitor, MGCD290, in combination with echinocandins against echinocandin-resistant Candida species, Diagn Microbiol Infect Dis, vol.81, issue.4, pp.259-63, 2015.

D. M. Kuhn, T. George, J. Chandra, P. K. Mukherjee, and M. A. Ghannoum, Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins, Antimicrob Agents Chemother, vol.46, issue.6, pp.1773-80, 2002.

A. Kawai, Y. Yamagishi, and H. Mikamo, In vitro efficacy of liposomal amphotericin B, micafungin and fluconazole against non-albicans Candida species biofilms, J Infect Chemother Off J Jpn Soc Chemother, vol.21, issue.9, pp.647-53, 2015.

H. T. Taff, K. F. Mitchell, J. A. Edward, and D. R. Andes, Mechanisms of Candida biofilm drug resistance, Future Microbiol, vol.8, issue.10, pp.1325-1362, 2013.

J. W. Song, J. H. Shin, S. J. Kee, S. H. Kim, M. G. Shin et al., Expression of CgCDR1, CgCDR2, and CgERG11 in Candida glabrata biofilms formed by bloodstream isolates, Med Mycol, vol.47, issue.5, pp.545-553, 2009.

L. Mathé and P. Van-dijck, Recent insights into Candida albicans biofilm resistance mechanisms, Curr Genet, 2013.

M. Martins, M. Henriques, J. L. Lopez-ribot, and R. Oliveira, Addition of DNase improves the in vitro activity of antifungal drugs against Candida albicans biofilms, Mycoses, vol.55, issue.1, pp.80-85, 2012.

A. B. Parsons, R. L. Brost, H. Ding, Z. Li, C. Zhang et al., Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways, Nat Biotechnol, vol.22, issue.1, pp.62-71, 2004.

D. A. Davis, How human pathogenic fungi sense and adapt to pH: the link to virulence, Curr Opin Microbiol, vol.12, issue.4, pp.365-70, 2009.

J. Gomez-raja and D. Da, The ?-arrestin-like protein Rim8 is hyperphosphorylated and complexes with Rim21 and Rim101 to promote adaptation to neutral-alkaline pH, Eukaryot Cell, vol.11, issue.5, pp.683-93, 2012.

M. Li, S. J. Martin, V. M. Bruno, A. P. Mitchell, and D. A. Davis, Candida albicans Rim13p, a Protease Required for Rim101p Processing at Acidic and Alkaline pHs, Eukaryot Cell, vol.3, issue.3, pp.741-51, 2004.

D. Davis, J. E. Edwards, A. P. Mitchell, and A. S. Ibrahim, Candida albicans RIM101 pH response pathway is required for host-pathogen interactions, Infect Immun, vol.68, issue.10, pp.5953-5962, 2000.

B. M. Mitchell, T. G. Wu, B. E. Jackson, and K. R. Wilhelmus, Candida albicans strain-dependent virulence and Rim13p-mediated filamentation in experimental keratomycosis, Invest Ophthalmol Vis Sci, vol.48, issue.2, pp.774-80, 2007.

C. J. Nobile, N. Solis, C. L. Myers, A. J. Fay, J. Deneault et al., Candida albicans transcription factor Rim101 mediates pathogenic interactions through cell wall functions, Cell Microbiol, vol.10, issue.11, pp.2180-96, 2008.

S. Cheng, C. J. Clancy, W. Xu, F. Schneider, B. Hao et al., Profiling of Candida albicans gene expression during intra-abdominal candidiasis identifies biologic processes involved in pathogenesis, J Infect Dis, vol.208, issue.9, pp.1529-1566, 2013.

E. S. Bensen, S. J. Martin, M. Li, J. Berman, and D. A. Davis, Transcriptional profiling in Candida albicans reveals new adaptive responses to extracellular pH and functions for Rim101p, Mol Microbiol, vol.54, issue.5, pp.1335-51, 2004.

M. Cornet and C. Gaillardin, pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies, vol.13, pp.342-52, 2014.

D. Bernardis, F. Mühlschlegel, F. A. Cassone, A. Fonzi, and W. A. , The pH of the host niche controls gene expression in and virulence of Candida albicans, Infect Immun, vol.66, issue.7, pp.3317-3342, 1998.

Y. Sun, C. Cao, W. Jia, L. Tao, G. Guan et al., pH Regulates White-Opaque Switching and Sexual Mating in Candida albicans, Eukaryot Cell, vol.14, issue.11, pp.1127-1161, 2015.

K. A. Marr, T. R. Rustad, J. H. Rex, and T. C. White, The trailing end point phenotype in antifungal susceptibility testing is pH dependent, Antimicrob Agents Chemother, vol.43, issue.6, pp.1383-1389, 1999.

M. Cornet, C. Gaillardin, and M. L. Richard, Deletions of the endocytic components VPS28 and VPS32 in Candida albicans lead to echinocandin and azole hypersensitivity, Antimicrob Agents Chemother, vol.50, issue.10, pp.3492-3497, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00164053

O. R. Homann, J. Dea, S. M. Noble, and A. D. Johnson, A phenotypic profile of the Candida albicans regulatory network, PLoS Genet, vol.5, issue.12, p.1000783, 2009.

J. M. Hollomon, N. Grahl, S. D. Willger, K. Koeppen, and D. A. Hogan, Global Role of Cyclic AMP Signaling in pH-Dependent Responses in Candida albicans. mSphere, vol.1, 2016.

P. Chua and G. S. Roeder, Bdf1, a yeast chromosomal protein required for sporulation, Mol Cell Biol, vol.15, issue.7, pp.3685-96, 1995.

J. Govin, J. Dorsey, J. Gaucher, S. Rousseaux, S. Khochbin et al., Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis, Genes Dev, vol.24, issue.16, pp.1772-86, 2010.

J. Fu, J. Hou, L. Liu, L. Chen, M. Wang et al., Interplay between BDF1 and BDF2 and their roles in regulating the yeast salt stress response, FEBS J, vol.280, issue.9, pp.1991-2001, 2013.

G. A. Josling, S. A. Selvarajah, M. Petter, and M. F. Duffy, The role of bromodomain proteins in regulating gene expression, Genes, vol.3, issue.2, pp.320-363, 2012.

C. Sawa, E. Nedea, N. Krogan, T. Wada, H. Handa et al., Bromodomain factor 1 (Bdf1) is phosphorylated by protein kinase CK2, Mol Cell Biol, vol.24, issue.11, pp.4734-4776, 2004.

A. G. Ladurner, C. Inouye, R. Jain, and R. Tjian, Bromodomains mediate an acetyl-histone encoded antisilencing function at heterochromatin boundaries, Mol Cell, vol.11, issue.2, pp.365-76, 2003.

Z. Xu, Y. Cao, J. Zhang, Y. Cao, P. Gao et al., cDNA array analysis of the differential expression change in virulence-related genes during the development of resistance in Candida albicans, Acta Biochim Biophys Sin Shanghai, vol.37, issue.7, pp.463-72, 2005.

S. M. Noble and A. D. Johnson, Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans, Eukaryot Cell, vol.4, issue.2, pp.298-309, 2005.

J. Branco, A. P. Silva, R. M. Silva, A. Silva-dias, C. Pina-vaz et al., Fluconazole and Voriconazole Resistance in Candida parapsilosis Is Conferred by Gain-of-Function Mutations in MRR1 Transcription Factor Gene, Antimicrob Agents Chemother, vol.59, issue.10, pp.6629-6662, 2015.

M. D. Leach, E. Klipp, L. E. Cowen, and A. Brown, Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs, Nat Rev Microbiol, vol.10, issue.10, pp.693-704, 2012.

R. Zhao and W. A. Houry, Hsp90: a chaperone for protein folding and gene regulation, Biochem Cell Biol Biochim Biol Cell, vol.83, issue.6, pp.703-713, 2005.

G. Chen, W. D. Bradford, C. W. Seidel, and R. Li, Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy, Nature, vol.482, issue.7384, pp.246-50, 2012.

J. Pachl, P. Svoboda, F. Jacobs, K. Vandewoude, B. Van-der-hoven et al., A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis, Clin Infect Dis Off Publ Infect Dis Soc Am, vol.42, issue.10, pp.1404-1417, 2006.

S. Amorim-vaz, E. Delarze, F. Ischer, D. Sanglard, and A. T. Coste, Examining the virulence of Candida albicans transcription factor mutants using Galleria mellonella and mouse infection models, Front Microbiol, vol.6, p.367, 2015.

D. Li, L. Deng, G. Hu, L. Zhao, D. Hu et al., Using Galleria mellonella-Candida albicans infection model to evaluate antifungal agents, Biol Pharm Bull, vol.36, issue.9, pp.1482-1489, 2013.

E. Delarze, F. Ischer, D. Sanglard, and A. T. Coste, Adaptation of a Gaussia princeps Luciferase reporter system in Candida albicans for in vivo detection in the Galleria mellonella infection model, Virulence, vol.6, issue.7, pp.684-93, 2015.

R. Santos, C. Costa, D. Mil-homens, D. Romão, C. De-carvalho et al., The multidrug resistance transporters CgTpo1_1 and CgTpo1_2 play a role in virulence and biofilm formation in the human pathogen Candida glabrata, Cell Microbiol, 2016.

M. Staniszewska, M. Bondaryk, M. Wieczorek, E. Estrada-mata, H. M. Mora-montes et al., Antifungal Effect of Novel 2-Bromo-2-Chloro-2-(4-Chlorophenylsulfonyl)-1-Phenylethanone against Candida Strains, Front Microbiol, vol.7, p.1309, 2016.