Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance �

The survival of all organisms depends critically upon interactions with the environment, mediated largely through the action of small molecules. Small molecules can provide the nutrients to support life ([195][1]), mediate communication between organisms ([25][2], [76][3], [238][4]), or exert

[1]  M. Colom,et al.  Antifungal Susceptibility of Cryptococcus neoformans Isolates in HIV-Infected Patients to Fluconazole, Itraconazole and Voriconazole in Spain: 1994–1996 and 1997–2005 , 2007, Chemotherapy.

[2]  James D. Griffin,et al.  Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia , 2007, Nature Reviews Cancer.

[3]  Guy Nimrod,et al.  Disruption of the Aspergillus fumigatus ECM33 homologue results in rapid conidial germination, antifungal resistance and hypervirulence. , 2006, Microbiology.

[4]  M. Pfaller,et al.  Rare and Emerging Opportunistic Fungal Pathogens: Concern for Resistance beyond Candida albicans and Aspergillus fumigatus , 2004, Journal of Clinical Microbiology.

[5]  N. Chauhan,et al.  The Ssk1p Response Regulator and Chk1p Histidine Kinase Mutants of Candida albicans Are Hypersensitive to Fluconazole and Voriconazole , 2007, Antimicrobial Agents and Chemotherapy.

[6]  J. Heitman,et al.  The Calcineurin Target, Crz1, Functions in Azole Tolerance but Is Not Required for Virulence of Candida albicans , 2004, Infection and Immunity.

[7]  Joseph Heitman,et al.  Synergistic Antifungal Activities of Bafilomycin A1, Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against Cryptococcus neoformans , 2000, Antimicrobial Agents and Chemotherapy.

[8]  D. Sanglard,et al.  Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents , 2003, Antimicrobial Agents and Chemotherapy.

[9]  T. C. White,et al.  Stable azole drug resistance associated with a substrain of Candida albicans from an HIV-infected patient. , 1997, Oral diseases.

[10]  M. J. Buitrago,et al.  Head-to-Head Comparison of the Activities of Currently Available Antifungal Agents against 3,378 Spanish Clinical Isolates of Yeasts and Filamentous Fungi , 2006, Antimicrobial Agents and Chemotherapy.

[11]  J. Perfect,et al.  Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  M. Mclaughlin,et al.  The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth. , 1994, Gene.

[13]  P. Skatrud,et al.  Cloning and characterization of CneMDR1: a Cryptococcus neoformans gene encoding a protein related to multidrug resistance proteins. , 1997, Gene.

[14]  M. Pfaller,et al.  In Vitro Activities of Caspofungin Compared with Those of Fluconazole and Itraconazole against 3,959 Clinical Isolates of Candida spp., Including 157 Fluconazole-Resistant Isolates , 2003, Antimicrobial Agents and Chemotherapy.

[15]  J. Heitman,et al.  Teaching old drugs new tricks: reincarnating immunosuppressants as antifungal drugs. , 2003, Current opinion in investigational drugs.

[16]  L. Piddock Multidrug-resistance efflux pumps ? not just for resistance , 2006, Nature Reviews Microbiology.

[17]  J. Wingard,et al.  Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia , 1997, Antimicrobial agents and chemotherapy.

[18]  B. Lebeau,et al.  Susceptibility testing of sequential isolates of Aspergillus fumigatus recovered from treated patients. , 2004, Journal of medical microbiology.

[19]  Grace Yim,et al.  Antibiotics as signalling molecules , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[20]  H. Bussey,et al.  Analysis of β-1,3-Glucan Assembly in Saccharomyces cerevisiae Using a Synthetic Interaction Network and Altered Sensitivity to Caspofungin , 2004, Genetics.

[21]  C. Selitrennikoff,et al.  Neurospora crassa FKS Protein Binds to the (1,3)β-Glucan Synthase Substrate, UDP-Glucose , 2003, Current Microbiology.

[22]  Rajinder Kumar,et al.  Plasmodium falciparum calcineurin and its association with heat shock protein 90: mechanisms for the antimalarial activity of cyclosporin A and synergism with geldanamycin. , 2005, Molecular and biochemical parasitology.

[23]  C. Selitrennikoff,et al.  Cryptococcus neoformans Resistance to Echinocandins: (1,3)β-Glucan Synthase Activity Is Sensitive to Echinocandins , 2005, Antimicrobial Agents and Chemotherapy.

[24]  J. Berman,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 , 2006, Genetics.

[25]  M. Pfaller,et al.  Global Trends in the Antifungal Susceptibility of Cryptococcus neoformans (1990 to 2004) , 2005, Journal of Clinical Microbiology.

[26]  J. Heitman,et al.  Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans. , 2006, Microbiology.

[27]  K. Bartizal,et al.  Characterization of echinocandin-resistant mutants of Candida albicans: genetic, biochemical, and virulence studies , 1996, Infection and immunity.

[28]  D. Kontoyiannis,et al.  Combination of caspofungin with inhibitors of the calcineurin pathway attenuates growth in vitro in Aspergillus species. , 2003, The Journal of antimicrobial chemotherapy.

[29]  D. Diogo,et al.  Genotypic Evolution of Azole Resistance Mechanisms in Sequential Candida albicans Isolates , 2007, Eukaryotic Cell.

[30]  M. Riley,et al.  Bacteriocins: evolution, ecology, and application. , 2002, Annual review of microbiology.

[31]  E. Mellado,et al.  Substitutions at Methionine 220 in the 14α-Sterol Demethylase (Cyp51A) of Aspergillus fumigatus Are Responsible for Resistance In Vitro to Azole Antifungal Drugs , 2004, Antimicrobial Agents and Chemotherapy.

[32]  J. Morschhäuser,et al.  Multiple cis-Acting Sequences Mediate Upregulation of the MDR1 Efflux Pump in a Fluconazole-Resistant Clinical Candida albicans Isolate , 2006, Antimicrobial Agents and Chemotherapy.

[33]  R. Homayouni,et al.  Genome-Wide Expression and Location Analyses of the Candida albicans Tac1p Regulon , 2007, Eukaryotic Cell.

[34]  Bonnie L. Bassler,et al.  Bacterial Small-Molecule Signaling Pathways , 2006, Science.

[35]  R. Cannon,et al.  Candida albicans drug resistance another way to cope with stress. , 2007, Microbiology.

[36]  D. Sanglard,et al.  Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance. , 2006, Microbiology.

[37]  E. Manavathu,et al.  Isolation and in vitro susceptibility to amphotericin B, itraconazole and posaconazole of voriconazole-resistant laboratory isolates of Aspergillus fumigatus. , 2001, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[38]  Joseph Heitman,et al.  In Vitro Interactions between Antifungals and Immunosuppressants against Aspergillus fumigatus Isolates from Transplant and Nontransplant Patients , 2004, Antimicrobial Agents and Chemotherapy.

[39]  L. Cowen,et al.  Divergence in Fitness and Evolution of Drug Resistance in Experimental Populations of Candida albicans , 2001, Journal of bacteriology.

[40]  J. Heitman,et al.  Calcineurin Inhibition or Mutation Enhances Cell Wall Inhibitors against Aspergillus fumigatus , 2007, Antimicrobial Agents and Chemotherapy.

[41]  E. Mellado,et al.  Identification of Two Different 14-α Sterol Demethylase-Related Genes (cyp51A and cyp51B) in Aspergillus fumigatus and Other Aspergillus species , 2001, Journal of Clinical Microbiology.

[42]  M. Pfaller,et al.  Effects of cilofungin (LY121019) on carbohydrate and sterol composition ofCandida albicans , 1989, European Journal of Clinical Microbiology and Infectious Diseases.

[43]  A. Warris,et al.  Multidrug resistance in Aspergillus fumigatus. , 2002, The New England journal of medicine.

[44]  C. Kauffman,et al.  Clinical efficacy of new antifungal agents. , 2006, Current opinion in microbiology.

[45]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[46]  J. Berlin,et al.  The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[47]  S. Kelly,et al.  Resistance to amphotericin B associated with defective sterol delta 8-->7 isomerase in a Cryptococcus neoformans strain from an AIDS patient. , 1994, FEMS microbiology letters.

[48]  R. Betts,et al.  Anidulafungin versus fluconazole for invasive candidiasis. , 2007, The New England journal of medicine.

[49]  J. Dupouy-Camet,et al.  Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. , 1994, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[50]  A. D. De Lucca,et al.  Harmful fungi in both agriculture and medicine. , 2007, Revista iberoamericana de micologia.

[51]  J. Thevelein,et al.  The G protein-coupled receptor Gpr1 and the Galpha protein Gpa2 act through the cAMP-protein kinase A pathway to induce morphogenesis in Candida albicans. , 2005, Molecular biology of the cell.

[52]  J. Berman,et al.  An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1 , 2008, Molecular microbiology.

[53]  A. Casadevall,et al.  The effect of the echinocandin analogue caspofungin on cell wall glucan synthesis by Cryptococcus neoformans. , 2000, The Journal of infectious diseases.

[54]  T. Edlind,et al.  Cyclic AMP Signaling Pathway Modulates Susceptibility of Candida Species and Saccharomyces cerevisiae to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors , 2003, Antimicrobial Agents and Chemotherapy.

[55]  M. J. Buitrago,et al.  Combined Activity In Vitro of Caspofungin, Amphotericin B, and Azole Agents against Itraconazole-Resistant Clinical Isolates of Aspergillus fumigatus , 2005, Antimicrobial Agents and Chemotherapy.

[56]  C. Clancy,et al.  The hidden danger of primary fluconazole prophylaxis for patients with AIDS. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[57]  C. Kumamoto,et al.  Transcriptional Regulation of MDR1, Encoding a Drug Efflux Determinant, in Fluconazole-Resistant Candida albicans Strains through an Mcm1p Binding Site , 2006, Eukaryotic Cell.

[58]  M. Cyert,et al.  Temperature-Induced Expression of YeastFKS2 Is under the Dual Control of Protein Kinase C and Calcineurin , 1998, Molecular and Cellular Biology.

[59]  J. Perfect,et al.  A Glucan Synthase FKS1 Homolog inCryptococcus neoformans Is Single Copy and Encodes an Essential Function , 1999, Journal of bacteriology.

[60]  A. Beauvais,et al.  Specific molecular features in the organization and biosynthesis of the cell wall of Aspergillus fumigatus. , 2005, Medical Mycology.

[61]  D. Perlin Resistance to echinocandin-class antifungal drugs. , 2007, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[62]  S. Abe,et al.  Antifungal drug susceptibility of Cryptococcus neoformans from clinical sources in Nairobi, Kenya , 2007, Mycoses.

[63]  A. Casadevall,et al.  Susceptibility of Cryptococcus neoformans Biofilms to Antifungal Agents In Vitro , 2006, Antimicrobial Agents and Chemotherapy.

[64]  F. Baldelli,et al.  Clinical Efficacy and Tolerability of Caspofungin in a Renal Transplant Patient with Aspergillus flavus Lung Infection: Case Report , 2006, Journal of chemotherapy.

[65]  M. Dierich,et al.  Epidemiology and outcome of infections due to Aspergillus terreus: 10‐year single centre experience , 2005, British journal of haematology.

[66]  L. Pearl,et al.  Structure and mechanism of the Hsp90 molecular chaperone machinery. , 2006, Annual review of biochemistry.

[67]  E. Mellado,et al.  A Point Mutation in the 14α-Sterol Demethylase Gene cyp51A Contributes to Itraconazole Resistance in Aspergillus fumigatus , 2003, Antimicrobial Agents and Chemotherapy.

[68]  T. G. Mitchell,et al.  Dynamic and Heterogeneous Mutations to Fluconazole Resistance in Cryptococcus neoformans , 2001, Antimicrobial Agents and Chemotherapy.

[69]  L. Cowen,et al.  Evolution of drug resistance in Candida albicans. , 2002, Annual review of microbiology.

[70]  J. Lopez-Ribot,et al.  In Vitro Activity of Caspofungin (MK-0991) against Candida albicans Clinical Isolates Displaying Different Mechanisms of Azole Resistance , 2002, Journal of Clinical Microbiology.

[71]  D. Kontoyiannis,et al.  Resistance to itraconazole in Aspergillus nidulans and Aspergillus fumigatus is conferred by extra copies of the A. nidulans P-450 14alpha-demethylase gene, pdmA. , 2001, The Journal of antimicrobial chemotherapy.

[72]  E. Mellado,et al.  Comparative in Vitro Activity of Voriconazole and Itraconazole Against Fluconazole-Susceptible and Fluconazole-Resistant Clinical Isolates of Candida Species from Spain , 1999, European Journal of Clinical Microbiology and Infectious Diseases.

[73]  I. Yahara,et al.  Role of HSP90 in Salt Stress Tolerance via Stabilization and Regulation of Calcineurin , 2000, Molecular and Cellular Biology.

[74]  G. Goldman,et al.  In Vitro Evolution of Itraconazole Resistance in Aspergillus fumigatus Involves Multiple Mechanisms of Resistance , 2004, Antimicrobial Agents and Chemotherapy.

[75]  J. Beney,et al.  The direct cost and incidence of systemic fungal infections. , 2002, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[76]  M. Pfaller,et al.  Characterization of Heteroresistance to Fluconazole among Clinical Isolates of Cryptococcus neoformans , 2003, Journal of Clinical Microbiology.

[77]  C. Parry,et al.  Azole Drug Resistance as a Cause of Clinical Relapse in AIDS Patients with Cryptococcal Meningitis , 1995, International journal of STD & AIDS.

[78]  R. Homayouni,et al.  Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents in Candida albicans , 2005, Antimicrobial Agents and Chemotherapy.

[79]  E. Anaissie,et al.  International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed and refractory candidemia , 2005, European Journal of Clinical Microbiology and Infectious Diseases.

[80]  D. Niederwieser,et al.  In-vitro testing of susceptibility to amphotericin B is a reliable predictor of clinical outcome in invasive aspergillosis. , 1998, The Journal of antimicrobial chemotherapy.

[81]  Steve A. Hernandez,et al.  Antifungal Therapy of Murine Aspergillus terreus Infection , 2004, Antimicrobial Agents and Chemotherapy.

[82]  D. Denning,et al.  Lack of correlation of in vitro amphotericin B susceptibility testing with outcome in a murine model of Aspergillus infection. , 2000, The Journal of antimicrobial chemotherapy.

[83]  K. Kuchler,et al.  Fungal ATP-binding cassette (ABC) transporters in drug resistance & detoxification. , 2006, Current drug targets.

[84]  I. Polacheck,et al.  Heteroresistance to Fluconazole and Voriconazole inCryptococcus neoformans , 1999, Antimicrobial Agents and Chemotherapy.

[85]  A. Mitchell,et al.  How to build a biofilm: a fungal perspective. , 2006, Current opinion in microbiology.

[86]  D. Sanglard,et al.  Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans , 2000, Antimicrobial Agents and Chemotherapy.

[87]  M. Pfaller,et al.  Antifungal Activities of Posaconazole, Ravuconazole, and Voriconazole Compared to Those of Itraconazole and Amphotericin B against 239 Clinical Isolates of Aspergillus spp. and Other Filamentous Fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000 , 2002, Antimicrobial Agents and Chemotherapy.

[88]  H. Bussey,et al.  Cell Wall Assembly in Saccharomyces cerevisiae , 2006, Microbiology and Molecular Biology Reviews.

[89]  Brian C. Baldwin,et al.  The Mutation T315A in Candida albicans Sterol 14α-Demethylase Causes Reduced Enzyme Activity and Fluconazole Resistance through Reduced Affinity* , 1997, The Journal of Biological Chemistry.

[90]  J. Takala,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. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[91]  F. Loor,et al.  Reversion of the P-glycoprotein-mediated multidrug resistance of cancer cells by FK-506 derivatives. , 1993, Anti-cancer drugs.

[92]  M. Adelson,et al.  Detection of Aspergillus fumigatus and a Mutation That Confers Reduced Susceptibility to Itraconazole and Posaconazole by Real-Time PCR and Pyrosequencing , 2005, Journal of Clinical Microbiology.

[93]  J. Heitman,et al.  Cyclic AMP-Dependent Protein Kinase Regulates Pseudohyphal Differentiation in Saccharomyces cerevisiae , 1999, Molecular and Cellular Biology.

[94]  David E. Levin,et al.  Cell Wall Integrity Signaling in Saccharomyces cerevisiae , 2005, Microbiology and Molecular Biology Reviews.

[95]  W. Melchers,et al.  A New Aspergillus fumigatus Resistance Mechanism Conferring In Vitro Cross-Resistance to Azole Antifungals Involves a Combination of cyp51A Alterations , 2007, Antimicrobial Agents and Chemotherapy.

[96]  D. Sanglard,et al.  CRZ1, a target of the calcineurin pathway in Candida albicans , 2006, Molecular microbiology.

[97]  S. Lindquist,et al.  Hsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi , 2005, Science.

[98]  D. Perlin,et al.  A Ser678Pro Substitution in Fks1p Confers Resistance to Echinocandin Drugs in Aspergillus fumigatus , 2007, Antimicrobial Agents and Chemotherapy.

[99]  P. Lambert Bacterial resistance to antibiotics: modified target sites. , 2005, Advanced drug delivery reviews.

[100]  W. Pratt,et al.  Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery 1 , 2003, Experimental biology and medicine.

[101]  S. Sanche,et al.  In Vitro Amphotericin B Resistance in Clinical Isolates of Aspergillus terreus, with a Head-to-Head Comparison to Voriconazole , 1999, Journal of Clinical Microbiology.

[102]  G. A. Scarborough,et al.  Direct demonstration of high affinity interactions of immunosuppressant drugs with the drug binding site of the human P-glycoprotein. , 1994, Molecular pharmacology.

[103]  A. Brakhage,et al.  The mitogen-activated protein kinase MpkA of Aspergillus fumigatus regulates cell wall signaling and oxidative stress response. , 2008, Fungal genetics and biology : FG & B.

[104]  S. Kelly,et al.  Itraconazole resistance in Aspergillus fumigatus , 1997, Antimicrobial agents and chemotherapy.

[105]  B. Oliver,et al.  Cloning and expression of pkaC and pkaR, the genes encoding the cAMP-dependent protein kinase of Aspergillus fumigatus , 2004, Mycopathologia.

[106]  D. Perlin,et al.  Characterization of Aspergillus fumigatus mutants with reduced susceptibility to caspofungin. , 2005, Medical mycology.

[107]  J. Galgiani,et al.  Comparison of the in vitro activities of the echinocandin LY303366, the pneumocandin MK-0991, and fluconazole against Candida species and Cryptococcus neoformans , 1997, Antimicrobial agents and chemotherapy.

[108]  K. Kuchler,et al.  The Candida albicans Cdr2p ATP‐binding cassette (ABC) transporter confers resistance to caspofungin , 2003, Molecular microbiology.

[109]  Joseph Heitman,et al.  Sensing the environment: lessons from fungi , 2007, Nature Reviews Microbiology.

[110]  J. Bennett,et al.  Alexander Fleming and the discovery of penicillin. , 2001, Advances in applied microbiology.

[111]  G. Fink,et al.  The three yeast A kinases have specific signaling functions in pseudohyphal growth. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[112]  R. Cannon,et al.  Overexpression of Candida albicans CDR1, CDR2, or MDR1 Does Not Produce Significant Changes in Echinocandin Susceptibility , 2006, Antimicrobial Agents and Chemotherapy.

[113]  S. Kelly,et al.  Molecular basis of resistance to azole antifungals. , 2002, Trends in molecular medicine.

[114]  E. Borel,et al.  In-vivo itraconazole resistance of Aspergillus fumigatus in systemic murine aspergillosis. EBGA Network. European research group on Biotypes and Genotypes of Aspergillus fumigatus. , 1999, Journal of medical microbiology.

[115]  D. Picard,et al.  Heat-shock protein 90, a chaperone for folding and regulation , 2002, Cellular and Molecular Life Sciences CMLS.

[116]  Ronald N. Jones,et al.  International Surveillance of Candida spp. and Aspergillus spp.: Report from the SENTRY Antimicrobial Surveillance Program (2003) , 2006, Journal of Clinical Microbiology.

[117]  N. Gow,et al.  Antifungal agents: mechanisms of action. , 2003, Trends in microbiology.

[118]  A. Mitchell,et al.  Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors , 1997, Antimicrobial agents and chemotherapy.

[119]  D. Perlin,et al.  Serum Differentially Alters the Antifungal Properties of Echinocandin Drugs , 2007, Antimicrobial Agents and Chemotherapy.

[120]  J. Vazquez,et al.  Reduced susceptibility in laboratory-selected mutants of Aspergillus fumigatus to itraconazole due to decreased intracellular accumulation of the antifungal agent. , 1999, International journal of antimicrobial agents.

[121]  L. Koymans,et al.  Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. , 1999, Microbiology.

[122]  Joseph Heitman,et al.  Calcineurin is essential for survival during membrane stress in Candida albicans , 2002, The EMBO journal.

[123]  T Watanabe,et al.  Identification of Yeast Rho1p GTPase as a Regulatory Subunit of 1,3-β-Glucan Synthase , 1996, Science.

[124]  M. Cyert,et al.  Calcineurin acts through the CRZ1/TCN1-encoded transcription factor to regulate gene expression in yeast. , 1997, Genes & development.

[125]  A. Casadevall,et al.  Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro , 1997, Antimicrobial agents and chemotherapy.

[126]  J. Burnie,et al.  Preclinical Assessment of the Efficacy of Mycograb, a Human Recombinant Antibody against Fungal HSP90 , 2003, Antimicrobial Agents and Chemotherapy.

[127]  P. R. Kraus,et al.  The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function , 2003, Molecular microbiology.

[128]  E. Borel,et al.  Acquired itraconazole resistance in Aspergillus fumigatus. , 2001, Journal of Antimicrobial Chemotherapy.

[129]  M. Ghannoum,et al.  Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B. , 2003, The Journal of infectious diseases.

[130]  Dominique Sanglard,et al.  Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence , 2003, Molecular microbiology.

[131]  D. Kontoyiannis,et al.  Aspergillus nidulans is frequently resistant to amphotericin B , 2002, Mycoses.

[132]  D. Denning,et al.  Correlation between in-vitro susceptibility testing to itraconazole and in-vivo outcome of Aspergillus fumigatus infection. , 1997, The Journal of antimicrobial chemotherapy.

[133]  Dominique Sanglard,et al.  Amino Acid Substitutions in the Cytochrome P-450 Lanosterol 14α-Demethylase (CYP51A1) from Azole-Resistant Candida albicans Clinical Isolates Contribute to Resistance to Azole Antifungal Agents , 1998, Antimicrobial Agents and Chemotherapy.

[134]  R. Homayouni,et al.  The Transcription Factor Mrr1p Controls Expression of the MDR1 Efflux Pump and Mediates Multidrug Resistance in Candida albicans , 2007, PLoS pathogens.

[135]  N. Morin,et al.  Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase , 1995, Molecular and cellular biology.

[136]  N. Morin,et al.  The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[137]  Russell E. Lewis,et al.  Attenuation of the Activity of Caspofungin at High Concentrations against Candida albicans: Possible Role of Cell Wall Integrity and Calcineurin Pathways , 2005, Antimicrobial Agents and Chemotherapy.

[138]  A. Mitchell,et al.  Genetics and genomics of Candida albicans biofilm formation , 2006, Cellular microbiology.

[139]  P. Skatrud,et al.  Genes encoding multiple drug resistance-like proteins in Aspergillus fumigatus and Aspergillus flavus. , 1997, Gene.

[140]  J. Sobel,et al.  Shuttle vectors for Candida albicans: control of plasmid copy number and elevated expression of cloned genes , 2004, Current Genetics.

[141]  D. Loebenberg,et al.  Mutations in Aspergillus fumigatus Resulting in Reduced Susceptibility to Posaconazole Appear To Be Restricted to a Single Amino Acid in the Cytochrome P450 14α-Demethylase , 2003, Antimicrobial Agents and Chemotherapy.

[142]  J. Heitman,et al.  A unique fungal two-component system regulates stress responses, drug sensitivity, sexual development, and virulence of Cryptococcus neoformans. , 2006, Molecular biology of the cell.

[143]  Kailash Gulshan,et al.  Multidrug Resistance in Fungi , 2007, Eukaryotic Cell.

[144]  Martha S. Cyert,et al.  Integration of Stress Responses: Modulation of Calcineurin Signaling in Saccharomyces cerevisiae by Protein Kinase A , 2004, Eukaryotic Cell.

[145]  L. Neckers,et al.  Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[146]  F. García-Bragado,et al.  Possible development of resistance to fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[147]  N. Wiederhold Attenuation of echinocandin activity at elevated concentrations: a review of the paradoxical effect , 2007, Current opinion in infectious diseases.

[148]  M. Pfaller,et al.  In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole , 2005, Journal of Clinical Microbiology.

[149]  E. Mellado,et al.  A Point Mutation in the 14α-Sterol Demethylase Gene cyp51A Contributes to Itraconazole Resistance in Aspergillus fumigatus , 2004, Antimicrobial Agents and Chemotherapy.

[150]  K. Kuchler,et al.  Reversal of antifungal resistance mediated by ABC efflux pumps from Candida albicans functionally expressed in yeast. , 2003, International journal of antimicrobial agents.

[151]  M.,et al.  I n-vivo it raconazole resistance of Aspergillus fumigatus in systemic murine aspergillosis , 2022 .

[152]  Anne E Carpenter,et al.  Genetic Architecture of Hsp90-Dependent Drug Resistance , 2006, Eukaryotic Cell.

[153]  C. d’Enfert Biofilms and their role in the resistance of pathogenic Candida to antifungal agents. , 2006, Current drug targets.

[154]  T. C. White,et al.  Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus , 1997, Antimicrobial agents and chemotherapy.

[155]  D. Denning,et al.  Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis , 2006, Journal of Infection.

[156]  J. Smith,et al.  Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis , 1997, Antimicrobial agents and chemotherapy.

[157]  C. Nombela,et al.  PST1 and ECM33 encode two yeast cell surface GPI proteins important for cell wall integrity. , 2004, Microbiology.

[158]  E. Mellado,et al.  Differences in Interactions between Azole Drugs Related to Modifications in the 14-α Sterol Demethylase Gene (cyp51A) of Aspergillus fumigatus , 2005, Antimicrobial Agents and Chemotherapy.

[159]  D. Perlin,et al.  Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. , 2006, The Journal of antimicrobial chemotherapy.

[160]  W. Doolittle,et al.  A kingdom-level phylogeny of eukaryotes based on combined protein data. , 2000, Science.

[161]  Joseph Heitman,et al.  Calcineurin Is Essential for Candida albicans Survival in Serum and Virulence , 2003, Eukaryotic Cell.

[162]  M. Rinaldi,et al.  In vitro susceptibilities of cerebrospinal fluid isolates of Cryptococcus neoformans collected during a ten‐year period against fluconazole, voriconazole and posaconazole (SCH56592) , 2002, Mycoses.

[163]  D. Sanglard,et al.  A common drug‐responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance , 2002, Molecular microbiology.

[164]  I. F. Larrinoa,et al.  Functional characterization of the Candida albicans CRZ1 gene encoding a calcineurin-regulated transcription factor , 2005, Current Genetics.

[165]  D. Denning Echinocandin antifungal drugs , 2003, The Lancet.

[166]  C. Higgins,et al.  Multiple molecular mechanisms for multidrug resistance transporters , 2007, Nature.

[167]  B. Plikaytis,et al.  Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[168]  D. Stevens,et al.  Escape of Candida from Caspofungin Inhibition at Concentrations above the MIC (Paradoxical Effect) Accomplished by Increased Cell Wall Chitin; Evidence for β-1,6-Glucan Synthesis Inhibition by Caspofungin , 2006, Antimicrobial Agents and Chemotherapy.

[169]  Sergey V. Balashov,et al.  Rapid, High-Throughput, Multiplex, Real-Time PCR for Identification of Mutations in the cyp51A Gene of Aspergillus fumigatus That Confer Resistance to Itraconazole , 2005, Journal of Clinical Microbiology.

[170]  Sergey V. Balashov,et al.  Assessing Resistance to the Echinocandin Antifungal Drug Caspofungin in Candida albicans by Profiling Mutations in FKS1 , 2006, Antimicrobial Agents and Chemotherapy.

[171]  L. Brion,et al.  Risk of resistance associated with fluconazole prophylaxis: systematic review. , 2007, The Journal of infection.

[172]  S. A. Parent,et al.  Specific Substitutions in the Echinocandin Target Fks1p Account for Reduced Susceptibility of Rare Laboratory and Clinical Candida sp. Isolates , 2005, Antimicrobial Agents and Chemotherapy.

[173]  D. Andes,et al.  Putative Role of β-1,3 Glucans in Candida albicans Biofilm Resistance , 2006, Antimicrobial Agents and Chemotherapy.

[174]  J. Berman,et al.  Aneuploidy and Isochromosome Formation in Drug-Resistant Candida albicans , 2006, Science.

[175]  Stuart L Schreiber,et al.  Small molecules: the missing link in the central dogma , 2005, Nature chemical biology.

[176]  M. Gottesman,et al.  Targeting multidrug resistance in cancer , 2006, Nature Reviews Drug Discovery.

[177]  James B. Anderson Evolution of antifungal-drug resistance: mechanisms and pathogen fitness , 2005, Nature Reviews Microbiology.

[178]  Itamar Shalit,et al.  Genomic Approach to Identification of Mutations Affecting Caspofungin Susceptibility in Saccharomyces cerevisiae , 2004, Antimicrobial Agents and Chemotherapy.

[179]  C. Douglas,et al.  A Saccharomyces cerevisiae mutant with echinocandin-resistant 1,3-beta-D-glucan synthase , 1994, Journal of bacteriology.

[180]  D. Kelly,et al.  Resistance to fluconazole and cross‐resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol Δ5,6‐desaturation , 1997, FEBS letters.

[181]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.

[182]  Alistair J. P. Brown,et al.  The PKC, HOG and Ca2+ signalling pathways co‐ordinately regulate chitin synthesis in Candida albicans , 2007, Molecular microbiology.

[183]  D. Sanglard,et al.  Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans , 2000, Antimicrobial Agents and Chemotherapy.

[184]  S. Kelly,et al.  Cross-resistance to polyene and azole drugs in Cryptococcus neoformans , 1995, Antimicrobial agents and chemotherapy.

[185]  Wei Zhao,et al.  Deletion of the Regulatory Subunit of Protein Kinase A in Aspergillus fumigatus Alters Morphology, Sensitivity to Oxidative Damage, andVirulence , 2006, Infection and Immunity.

[186]  J. Perfect,et al.  Comparison of caspofungin and amphotericin B for invasive candidiasis. , 2002, The New England journal of medicine.

[187]  M. Ghannoum,et al.  New targets and delivery systems for antifungal therapy. , 2000, Medical mycology.

[188]  J. Smith,et al.  In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872) , 1997, Antimicrobial agents and chemotherapy.

[189]  D. Kelly,et al.  Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains , 1998, Antimicrobial Agents and Chemotherapy.

[190]  T. C. White,et al.  Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance , 1998, Clinical Microbiology Reviews.

[191]  M. Ghannoum,et al.  Evaluation of Possible Correlations between Antifungal Susceptibilities of Filamentous Fungi In Vitro and Antifungal Treatment Outcomes in Animal Infection Models , 1998, Antimicrobial Agents and Chemotherapy.

[192]  J. Perfect,et al.  Drug resistance in Cryptococcus neoformans. , 1999, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[193]  E. Borel,et al.  Sterol composition of itraconazole-resistant and itraconazole-susceptible isolates of Aspergillus fumigatus. , 2001, Canadian journal of microbiology.

[194]  Karl Kuchler,et al.  The Yeast Protein Kinase C Cell Integrity Pathway Mediates Tolerance to the Antifungal Drug Caspofungin through Activation of Slt2p Mitogen-Activated Protein Kinase Signaling , 2003, Eukaryotic Cell.

[195]  D. Denning,et al.  Activity of micafungin (FK463) against an itraconazole-resistant strain of Aspergillus fumigatus and a strain of Aspergillus terreus demonstrating in vivo resistance to amphotericin B. , 2003, Journal of Antimicrobial Chemotherapy.

[196]  C. Hoermann,et al.  Caspofungin‐resistant Aspergillus flavus after heart transplantation and mechanical circulatory support: a case report , 2008, Transplant infectious disease : an official journal of the Transplantation Society.

[197]  L. Cowen,et al.  Evolution of Drug Resistance in Experimental Populations of Candida albicans , 2000, Journal of bacteriology.

[198]  L. Pearl,et al.  Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. , 1999, Journal of medicinal chemistry.

[199]  J. Heitman,et al.  Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections , 2007, Nature Reviews Microbiology.

[200]  Russell E. Lewis,et al.  Aspergillus Susceptibility Testing in Patients with Cancer and Invasive Aspergillosis: Difficulties in Establishing Correlation Between In Vitro Susceptibility Data and the Outcome of Initial Amphotericin B Therapy , 2005, Pharmacotherapy.

[201]  J. Heitman,et al.  Ergosterol Biosynthesis Inhibitors Become Fungicidal when Combined with Calcineurin Inhibitors against Candida albicans, Candida glabrata, and Candida krusei , 2003, Antimicrobial Agents and Chemotherapy.

[202]  R. Prasad,et al.  Structure and Function Analysis of CaMdr1p, a Major Facilitator Superfamily Antifungal Efflux Transporter Protein of Candida albicans: Identification of Amino Acid Residues Critical for Drug/H+ Transport , 2007, Eukaryotic Cell.

[203]  A. Rodrigues,et al.  Susceptibility of environmental versus clinical strains of pathogenic Aspergillus. , 2007, International journal of antimicrobial agents.

[204]  D. Ellis Amphotericin B: spectrum and resistance. , 2002, The Journal of antimicrobial chemotherapy.

[205]  D. Davis,et al.  Adaptation to environmental pH: integrating the Rim101 and calcineurin signal transduction pathways , 2007, Molecular microbiology.

[206]  D. Sanglard,et al.  Fungicidal Synergism of Fluconazole and Cyclosporine in Candida albicans Is Not Dependent on Multidrug Efflux Transporters Encoded by the CDR1, CDR2, CaMDR1, and FLU1 Genes , 2003, Antimicrobial Agents and Chemotherapy.

[207]  D. Perlin,et al.  Progressive Esophagitis Caused by Candida albicans with Reduced Susceptibility to Caspofungin , 2006, Pharmacotherapy.

[208]  Mark S Butler,et al.  Natural products--the future scaffolds for novel antibiotics? , 2006, Biochemical pharmacology.

[209]  M. Pfaller,et al.  Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem , 2007, Clinical Microbiology Reviews.

[210]  Joseph Heitman,et al.  Calcineurin Is Required for Candida albicans To Survive Calcium Stress in Serum , 2005, Infection and Immunity.

[211]  J. Heitman,et al.  Good fungi gone bad: The corruption of calcineurin , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[212]  M. Gustin,et al.  Mitogen activated protein kinases of Aspergillus fumigatus. , 2005, Medical mycology.

[213]  A. Gunatilaka Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity, and implications of their occurrence. , 2006, Journal of natural products.

[214]  K. S. Lam,et al.  New aspects of natural products in drug discovery. , 2007, Trends in microbiology.

[215]  D. Sanglard,et al.  TAC1, Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2 , 2004, Eukaryotic Cell.

[216]  R. Béliveau,et al.  Molecular Interactions of Cyclosporin A with P-glycoprotein , 1997, The Journal of Biological Chemistry.

[217]  David Y. Thomas,et al.  Population genomics of drug resistance in Candida albicans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[218]  S. Kelly,et al.  Fluconazole tolerance in clinical isolates of Cryptococcus neoformans , 1997, Antimicrobial agents and chemotherapy.

[219]  A. Brakhage,et al.  The Cyclic AMP-Dependent Protein Kinase A Network Regulates Development and Virulence in Aspergillus fumigatus , 2004, Infection and Immunity.

[220]  J. Perfect,et al.  Emerging echinocandins for treatment of invasive fungal infections , 2006, Expert opinion on emerging drugs.

[221]  G. Alangaden,et al.  Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis. , 2002, The Journal of antimicrobial chemotherapy.

[222]  Anthony J. De Lucca Hongos patógenos communes en la Agricultura y la Medicina , 2007 .

[223]  M. Pfaller,et al.  Caspofungin Activity against Clinical Isolates of Fluconazole-Resistant Candida , 2003, Journal of Clinical Microbiology.

[224]  G. Fadda,et al.  Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter‐encoding gene, CnAFR1, involved in the resistance to fluconazole , 2003, Molecular microbiology.

[225]  D. Andes,et al.  Candida albicans biofilm development, modeling a host-pathogen interaction. , 2006, Current opinion in microbiology.

[226]  W. Melchers,et al.  Multiple-triazole-resistant aspergillosis. , 2007, The New England journal of medicine.

[227]  G. Goldman,et al.  Multiple Resistance Mechanisms among Aspergillus fumigatus Mutants with High-Level Resistance to Itraconazole , 2003, Antimicrobial Agents and Chemotherapy.

[228]  William R. Kirkpatrick,et al.  Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus , 2006, Eukaryotic Cell.

[229]  A. Mitchell,et al.  Regulation of azole drug susceptibility by Candida albicans protein kinase CK2 , 2005, Molecular microbiology.

[230]  T. Sterling,et al.  Resistance to amphotericin B: emerging clinical and microbiological patterns. , 1998, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[231]  D. Stevens,et al.  Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[232]  L. Cowen,et al.  The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype , 2008, Nature Reviews Microbiology.

[233]  J. Bennett,et al.  Fungal secondary metabolism — from biochemistry to genomics , 2005, Nature Reviews Microbiology.

[234]  D. Hogan Talking to Themselves: Autoregulation and Quorum Sensing in Fungi , 2006, Eukaryotic Cell.

[235]  J. Heitman,et al.  In Vitro Interactions between Antifungals and Immunosuppressants against Aspergillus fumigatus , 2004, Antimicrobial Agents and Chemotherapy.

[236]  Jason C. Young,et al.  Hsp90: a specialized but essential protein-folding tool. , 2001, The Journal of cell biology.

[237]  W. Houry,et al.  Hsp90: a chaperone for protein folding and gene regulation. , 2005, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[238]  D. Denning,et al.  Multi-azole resistance in Aspergillus fumigatus. , 2006, International journal of antimicrobial agents.

[239]  P. Cahn,et al.  G484S Amino Acid Substitution in Lanosterol 14-α Demethylase (ERG11) Is Related to Fluconazole Resistance in a Recurrent Cryptococcus neoformans Clinical Isolate , 2003, Antimicrobial Agents and Chemotherapy.

[240]  J. Lopez-Ribot,et al.  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 , 2001, Antimicrobial Agents and Chemotherapy.

[241]  D. Denning,et al.  Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate. , 2002, Fungal genetics and biology : FG & B.

[242]  J. Bennett,et al.  Fluconazole Treatment Is Effective against a Candida albicans erg3/erg3 Mutant In Vivo Despite In Vitro Resistance , 2006, Antimicrobial Agents and Chemotherapy.

[243]  C. Nombela,et al.  The GPI-anchored protein CaEcm33p is required for cell wall integrity, morphogenesis and virulence in Candida albicans. , 2004, Microbiology.