The fungal resistome: A risk and an opportunity for the development of novel antifungal therapies

Future Medicinal Chemistry

Volumn 8, Issue 12, 2016, Pages 1503-1520

  Reales Calderón, Jose A ^a,b,c   Molero, Gloria ^a,c   Gil, Concha ^a,c,d   Martínez, José L ^b  

^a UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^b CENTRO NACIONAL DE BIOTECNOLOGÍA   (Spain)

^c INSTITUTO RAMÓN Y CAJAL DE INVESTIGACIÓN SANITARIA IRYCIS   (Spain)

^d UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

Author keywords

chemosensitizer; clinical resistance; collateral sensitivity; inhibitor of resistance; intrinsic resistome

Indexed keywords

ANTIFUNGAL AGENT;

ANTIBIOTIC RESISTANCE; ANTIFUNGAL RESISTANCE; APOPTOSIS; BIOSYNTHESIS; CELL DEATH; DNA SYNTHESIS; DRUG EFFICACY; FUNGAL CELL WALL; GENETIC CODE; GENOMIC INSTABILITY; IMMUNOSTIMULATION; MINIMUM INHIBITORY CONCENTRATION; MYCOSIS; NONHUMAN; PRIORITY JOURNAL; REVIEW; RISK FACTOR; RNA SYNTHESIS; STRESS; CHEMISTRY; DRUG EFFECTS; FUNGUS; HUMAN; MICROBIAL SENSITIVITY TEST; MICROBIOLOGY; MYCOSES; PHYSIOLOGY; SYNTHESIS;

ANTIFUNGAL AGENTS; DRUG RESISTANCE, FUNGAL; FUNGI; HUMANS; MICROBIAL SENSITIVITY TESTS; MYCOSES;

EID: 84982107139     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc-2016-0051     Document Type: Review

References (153)

1. Pradhan NP, Bhat SM, Ghadage DP. Nosocomial infections in the medical ICU: a retrospective study highlighting their prevalence, microbiological profile and impact on ICU stay and mortality. J. Assoc. Physicians India 62(10), 18-21 (2014).
2. Sarabahi S, Tiwari VK, Arora S, Capoor MR, Pandey A. Changing pattern of fungal infection in burn patients. Burns 38(4), 520-528 (2012).
3. Devrim I, Demirag B, Yaman Y et al. A 7-year study of the distribution of nosocomial candidemia in children with cancer. Turk. J. Pediatr. 57(3), 225-229 (2015).
4. Tezer H, Canpolat FE, Dilmen U. Invasive fungal infections during the neonatal period: diagnosis, treatment and prophylaxis. Expert Opin. Pharmacother. 13(2), 193-205 (2012).
5. Alangaden GJ. Nosocomial fungal infections: epidemiology, infection control, and prevention. Infect. Dis. Clin. North Am. 25(1), 201-225 (2011).
6. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin. Infect. Dis. 39(3), 309-317 (2004).
7. Low CY, Rotstein C. Emerging fungal infections in immunocompromised patients. F1000 Med. Rep. 3, 14 (2011).
8. Vanden Bossche H, Willemsens G, Marichal P. Anti-Candida drugs-the biochemical basis for their activity. Crit. Rev. Microbiol. 15(1), 57-72 (1987).
9. Martinez JL, Coque TM, Baquero F. What is a resistance gene? Ranking risk in resistomes. Nat. Rev. Microbiol. 13(2), 116-123 (2015).
10. Martinez JL, Fajardo A, Garmendia L et al. A global view of antibiotic resistance. FEMS Microbiol. Rev. 33(1), 44-65 (2009).
11. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74(3), 417-433 (2010).
12. Alekshun MN, Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell 128(6), 1037-1050 (2007).
13. Prasad R, Shah AH, Rawal MK. Antifungals: mechanism of action and drug resistance. Adv. Exp. Med. Biol. 892, 327-349 (2016).
14. Vandeputte P, Ferrari S, Coste AT. Antifungal resistance and new strategies to control fungal infections. Int. J. Microbiol. 2012, 713687 (2012).
15. Marichal P, Koymans L, Willemsens S et al. Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology 145(Pt 10), 2701-2713 (1999).
16. Dodgson AR, Dodgson KJ, Pujol C, Pfaller MA, Soll DR. Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob. Agents Chemother. 48(6), 2223-2227 (2004).
17. Denning DW, Hope WW. Therapy for fungal diseases: opportunities and priorities. Trends Microbiol. 18(5), 195-204 (2010).
18. Bush K. Beta-lactamase inhibitors from laboratory to clinic. Clin. Microbiol. Rev. 1(1), 109-123 (1988).
19. Orozco AS, Higginbotham LM, Hitchcock CA et al. Mechanism of fluconazole resistance in Candida krusei. Antimicrob. Agents Chemother. 42(10), 2645-2649 (1998).
20. Feldmesser M, Kress Y, Mednick A, Casadevall A. The effect of the echinocandin analogue caspofungin on cell wall glucan synthesis by Cryptococcus neoformans. J. Infect. Dis. 182(6), 1791-1795 (2000).
21. Sionov E, Chang YC, Garraffo HM, Kwon-Chung KJ. Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob. Agents Chemother. 53(7), 2804-2815 (2009).
22. Pfaller MA, Diekema DJ. Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus. J. Clin. Microbiol. 42(10), 4419-4431 (2004).
23. Blinkhorn RJ, Adelstein D, Spagnuolo PJ. Emergence of a new opportunistic pathogen, Candida lusitaniae. J. Clin. Microbiol. 27(2), 236-240 (1989).
24. Walsh TJ, Salkin IF, Dixon DM, Hurd NJ. Clinical, microbiological, and experimental animal studies of Candida lipolytica. J. Clin. Microbiol. 27(5), 927-931 (1989).
25. Dick JD, Rosengard BR, Merz WG, Stuart RK, Hutchins GM, Saral R. Fatal disseminated candidiasis due to amphotericin-B-resistant Candida guilliermondii. Ann. Intern. Med. 102(1), 67-68 (1985).
26. Anaissie E, Bodey GP. Disseminated trichosporonosis: meeting the challenge. Eur. J. Clin. Microbiol. Infect. Dis. 10(9), 711-713 (1991).
27. Walsh TJ, Melcher GP, Rinaldi MG et al. Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. J. Clin. Microbiol. 28(7), 1616-1622 (1990).
28. Abraham OC, Manavathu EK, Cutright JL, Chandrasekar PH. In vitro susceptibilities of Aspergillus species to voriconazole, itraconazole, and amphotericin B. Diagn. Microbiol. Infect. Dis. 33(1), 7-11 (1999).
29. Tomsikova A. Causative agents of nosocomial mycoses. Folia Microbiol. (Praha) 47(2), 105-112 (2002).
30. Moran GP, Sullivan DJ, Henman MC et al. Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro. Antimicrob. Agents Chemother. 41(3), 617-623 (1997).
31. Sugita T, Takeo K, Ohkusu M et al. Fluconazole-resistant pathogens Candida inconspicua and C. norvegensis: DNA sequence diversity of the rRNA intergenic spacer region, antifungal drug susceptibility, and extracellular enzyme production. Microbiol. Immunol. 48(10), 761-766 (2004).
32. Sandven P, Nilsen K, Digranes A, Tjade T, Lassen J. Candida norvegensis: a fluconazole-resistant species. Antimicrob. Agents Chemother. 41(6), 1375-1376 (1997).
33. Warrilow AG, Melo N, Martel CM et al. Expression, purification, and characterization of Aspergillus fumigatus sterol 14-alpha demethylase (CYP51) isoenzymes A and B. Antimicrob. Agents Chemother. 54(10), 4225-4234 (2010).
34. Orni-Wasserlauf R, Izkhakov E, Siegman-Igra Y, Bash E, Polacheck I, Giladi M. Fluconazole-resistant Cryptococcus neoformans isolated from an immunocompetent patient without prior exposure to fluconazole. Clin. Infect. Dis. 29(6), 1592-1593 (1999).
35. Varma A, Kwon-Chung KJ. Heteroresistance of Cryptococcus gattii to fluconazole. Antimicrob. Agents Chemother. 54(6), 2303-2311 (2010).
36. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am. J. Med. 125(Suppl. 1), S3-S13 (2012).
37. Walker LA, Gow NA, Munro CA. Fungal echinocandin resistance. Fungal Genet. Biol. 47(2), 117-126 (2010).
38. Ha YS, Covert SF, Momany M. FsFKS1, the 1,3-beta-glucan synthase from the caspofungin-resistant fungus Fusarium solani. Eukaryot. Cell 5(7), 1036-1042 (2006).
39. Perlin DS. Antifungal drug resistance: do molecular methods provide a way forward? Curr. Opin. Infect. Dis. 22(6), 568-573 (2009).
40. Kelly SL, Lamb DC, Corran AJ, Baldwin BC, Kelly DE. Mode of action and resistance to azole antifungals associated with the formation of 14-alpha-methylergosta-8,24(28)-dien-3-beta,6-alpha-diol. Biochem. Biophys. Res. Commun. 207(3), 910-915 (1995).
41. Butters JA, Hollomon DW. Molecular analysis of azole fungicide resistance in a mutant of Ustilago maydis. Pestic. Sci. 46(3), 278-280 (1996).
42. Chen SCA, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 71(1), 11-41 (2011).
43. Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS. A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob. Agents Chemother. 52(7), 2305-2312 (2008).
44. Katiyar S, Pfaller M, Edlind T. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob. Agents Chemother. 50(8), 2892-2894 (2006).
45. Nascimento AM, Goldman GH, Park S et al. Multiple resistance mechanisms among Aspergillus fumigatus mutants with high-level resistance to itraconazole. Antimicrob. Agents Chemother. 47(5), 1719-1726 (2003).
46. Dannaoui E, Persat F, Monier MF, Borel E, Piens MA, Picot S. In-vitro susceptibility of Aspergillus spp. isolates to amphotericin B and itraconazole. J. Antimicrob. Chemother. 44(4), 553-555 (1999).
47. Marichal P, Vandenbossche H, Odds FC et al. Molecularbiological characterization of an azole-resistant Candida glabrata isolate. Antimicrob. Agents Chemother. 41(10), 2229-2237 (1997).
48. Olivares J, Bernardini A, Garcia-Leon G, Corona F, B Sanchez M, Martinez JL. The intrinsic resistome of bacterial pathogens. Front. Microbiol. 4, 103 (2013).
49. Fernandez L, Alvarez-Ortega C, Wiegand I et al. Characterization of the polymyxin B resistome of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 57, 110-119 (2013).
50. Cox G, Wright GD. Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int. J. Med. Microbiol. 303(6-7), 287-292 (2013).
51. Martinez JL. The antibiotic resistome: challenge and opportunity for therapeutic intervention. Future Med. Chem. 4(1756-8927), 347-359 (2012).
52. Alvarez-Ortega C, Wiegand I, Olivares J, Hancock RE, Martinez JL. The intrinsic resistome of Pseudomonas aeruginosa to beta-lactams. Virulence 2(2), 144-146 (2011).
53. Alvarez-Ortega C, Wiegand I, Olivares J, Hancock RE, Martinez JL. Genetic determinants involved in the susceptibility of Pseudomonas aeruginosa to beta-lactam antibiotics. Antimicrob. Agents Chemother. 54(10), 4159-4167 (2010).
54. Tamae C, Liu A, Kim K et al. Determination of antibiotic hypersensitivity among 4,000 single-gene-knockout mutants of Escherichia coli. J. Bacteriol. 190(17), 5981-5988 (2008).
55. Fajardo A, Martinez-Martin N, Mercadillo M et al. The neglected intrinsic resistome of bacterial pathogens. PLoS ONE 3(2), e1619 (2008).
56. Ramage G, Bachmann S, Patterson TF, Wickes BL, Lopez-Ribot JL. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J. Antimicrob. Chemother. 49(6), 973-980 (2002).
57. Sanglard D, Ischer F, Monod M, Bille J. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob. Agents Chemother. 40(10), 2300-2305 (1996).
58. Sun N, Fonzi W, Chen H et al. Azole susceptibility and transcriptome profiling in Candida albicans mitochondrial electron transport chain complex I mutants. Antimicrob. Agents Chemother. 57(1), 532-542 (2013).
59. Jensen-Pergakes KL, Kennedy MA, Lees ND, Barbuch R, Koegel C, Bard M. Sequencing, disruption, and characterization of the Candida albicans sterol methyltransferase (ERG6) gene: drug susceptibility studies in erg6 mutants. Antimicrob. Agents Chemother. 42(5), 1160-1167 (1998).
60. Boisnard S, Ruprich-Robert G, Florent M, Da Silva B, Chapeland-Leclerc F, Papon N. Role of Sho1p adaptor in the pseudohyphal development, drugs sensitivity, osmotolerance and oxidant stress adaptation in the opportunistic yeast Candida lusitaniae. Yeast 25(11), 849-859 (2008).
61. Vandeputte P, Tronchin G, Rocher F et al. Hypersusceptibility to azole antifungals in a clinical isolate of Candida glabrata with reduced aerobic growth. Antimicrob. Agents Chemother. 53(7), 3034-3041 (2009).
62. Jain P, Akula I, Edlind T. Cyclic AMP signaling pathway modulates susceptibility of Candida species and Saccharomyces cerevisiae to antifungal azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents Chemother. 47(10), 3195-3201 (2003).
63. Simonetti G, Villa A, Simonetti N. Inhibition of resistance and virulence in itraconazole-resistant Candida albicans by butylated hydroxyanisole. J. Chemother. 15(1), 91-92 (2003).
64. Mago N, Khuller GK. Influence of lipid-composition on the sensitivity of Candida albicans to antifungal agents. Indian J. Biochem. Biophys. 26(1), 30-33 (1989).
65. Venkateswarlu K, Denning DW, Manning NJ, Kelly SL. Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance. Antimicrob. Agents Chemother. 40(11), 2443-2446 (1996).
66. Maccallum DM, Coste A, Ischer F, Jacobsen MD, Odds FC, Sanglard D. Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection. Antimicrob. Agents Chemother. 54(4), 1476-1483 (2010).
67. Prasad R, Dewergifosse P, Goffeau A, Balzi E. Molecularcloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr. Genet. 27(4), 320-329 (1995).
68. Posteraro B, Sanguinetti M, Sanglard D et al. Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol. Microbiol. 47(2), 357-371 (2003).
69. Hitchcock CA, Barrett-Bee KJ, Russell NJ. The lipid composition and permeability to azole of an azole-and polyene-resistant mutant of Candida albicans. J. Med. Vet. Mycol. 25(1), 29-37 (1987).
70. Whelan WL. The Genetic-basis of resistance to 5-fluorocytosine in Candida species and Cryptococcus neoformans. CRC Crit. Rev. Microbiol. 15(1), 45-56 (1987).
71. Barchiesi F, Arzeni D, Caselli F, Scalise G. Primary resistance to flucytosine among clinical isolates of Candida spp. J. Antimicrob. Chemother. 45(3), 408-409 (2000).
72. Vanden Bossche H, Marichal P, Odds FC. Molecular mechanisms of drug resistance in fungi. Trends Microbiol. 2(10), 393-400 (1994).
73. Coyle S, Kroll E. Starvation induces genomic rearrangements and starvation-resilient phenotypes in yeast. Mol. Biol. Evol. 25(2), 310-318 (2008).
74. Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313(5785), 367-370 (2006).
75. Kraus E, Leung WY, Haber JE. Break-induced replication: a review and an example in budding yeast. Proc. Natl Acad. Sci. USA 98(15), 8255-8262 (2001).
76. Covo S, Puccia CM, Argueso JL, Gordenin DA, Resnick MA. The sister chromatid cohesion pathway suppresses multiple chromosome gain and chromosome amplification. Genetics 196(2), 373-384 (2014).
77. Dunkel N, Blass J, Rogers PD, Morschhauser J. Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol. Microbiol. 69(4), 827-840 (2008).
78. Zhu J, Pavelka N, Bradford WD, Rancati G, Li R. Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet. 8(5), e1002719 (2012).
79. Pavelka N, Rancati G. Never in neutral: a systems biology and evolutionary perspective on how aneuploidy contributes to human diseases. Cytogenet. Genome Res. 139(3), 193-205 (2013).
80. Morrow CA, Fraser JA. Ploidy variation as an adaptive mechanism in human pathogenic fungi. Semin. Cell Dev. Biol. 24(4), 339-346 (2013).
81. Sionov E, Chang YC, Kwon-Chung KJ. Azole heteroresistance in Cryptococcus neoformans: emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment. Antimicrob. Agents Chemother. 57(10), 5127-5130 (2013).
82. Tan ZH, Hays M, Cromie GA et al. Aneuploidy underlies a multicellular phenotypic switch. Proc. Natl Acad. Sci. USA 110(30), 12367-12372 (2013).
83. Pavelka N, Rancati G, Zhu J et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468(7321), 321-325 (2010).
84. Torres EM, Williams BR, Amon A. Aneuploidy: cells losing their balance. Genetics 179(2), 737-746 (2008).
85. Semighini CP, Averette AF, Perfect JR, Heitman J. Deletion of Cryptococcus neoformans AIF ortholog promotes chromosome aneuploidy and fluconazole-resistance in a metacaspase-independent manner. PLoS Pathog. 7(11), e1002364 (2011).
86. Ni M, Feretzaki M, Li W et al. Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans. PLoS Biol. 11(9), e1001653 (2013).
87. Selmecki A, Bergmann S, Berman J. Comparative genome hybridization reveals widespread aneuploidy in Candida albicans laboratory strains. Mol. Microbiol. 55(5), 1553-1565 (2005).
88. Kovalchuk A, Driessen AJ. Phylogenetic analysis of fungal ABC transporters. BMC Genomics 11, 177 (2010).
89. Pao SS, Paulsen IT, Saier MH Jr. Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62(1), 1-34 (1998).
90. Paumi CM, Chuk M, Snider J, Stagljar I, Michaelis S. ABC transporters in Saccharomyces cerevisiae and their interactors: new technology advances the biology of the ABCC (MRP) subfamily. Microbiol. Mol. Biol. Rev. 73(4), 577-593 (2009).
91. Kolaczkowski M, Kolaczkowska A, Motohashi N, Michalak K. New high-throughput screening assay to reveal similarities and differences in inhibitory sensitivities of multidrug ATP-binding cassette transporters. Antimicrob. Agents Chemother. 53(4), 1516-1527 (2009).
92. Niimi K, Harding DR, Parshot R et al. Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative. Antimicrob. Agents Chemother. 48(4), 1256-1271 (2004).
93. Kim J, Campbell B, Mahoney N, Chan K, Molyneux R, May G. Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs. Biochem. Biophys. Res. Commun. 372(1), 266-271 (2008).
94. Lamping E, Monk BC, Niimi K et al. Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot. Cell 6(7), 1150-1165 (2007).
95. Tanabe K, Lamping E, Adachi K et al. Inhibition of fungal ABC transporters by unnarmicin A and unnarmicin C, novel cyclic peptides from marine bacterium. Biochem. Biophys. Res. Commun. 364(4), 990-995 (2007).
96. Maesaki S, Marichal P, Hossain MA, Sanglard D, Vanden Bossche H, Kohno S. Synergic effects of tactolimus and azole antifungal agents against azole-resistant Candida albicans strains. J. Antimicrob. Chemother. 42(6), 747-753 (1998).
97. Cruz MC, Goldstein AL, Blankenship JR et al. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J. 21(4), 546-559 (2002).
98. Digirolamo JA, Li XC, Jacob MR, Clark AM, Ferreira D. Reversal of fluconazole resistance by sulfated sterols from the marine sponge topsentia sp. J. Nat. Prod. 72(8), 1524-1528 (2009).
99. Holmes AR, Lin YH, Niimi K et al. ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrob. Agents Chemother. 52(11), 3851-3862 (2008).
100. Yamamoto S, Hiraga K, Abiko A, Hamanaka N, Oda K. A new function of isonitrile as an inhibitor of the Pdr5p multidrug ABC transporter in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 330(2), 622-628 (2005).
101. Lee MD, Galazzo JL, Staley AL et al. Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco 56(1-2), 81-85 (2001).
102. Szczepaniak J, Lukaszewicz M, Krasowska A. Detection of inhibitors of Candida albicans Cdr transporters using a diS-C-3(3) fluorescence. Front. Microbiol. 6, 176 (2015).
103. Shukla S, Sauna ZE, Prasad R, Ambudkar SV. Disulfiram is a potent modulator of multidrug transporter Cdr1p of Candida albicans. Biochem. Biophys. Res. Commun. 322(2), 520-525 (2004).
104. Pina-Vaz C, Sansonetty F, Rodrigues AG, Martinez-De-Oliveira J, Fonseca AF, Mardh PA. Antifungal activity of ibuprofen alone and in combination with fluconazole against Candida species. J. Med. Microbiol. 49(9), 831-840 (2000).
105. Lemoine RC, Glinka TW, Watkins WJ et al. Quinazolinonebased fungal efflux pump inhibitors. Part 1: discovery of an (N-methylpiperazine)-containing derivative with activity in clinically relevant Candida spp. Bioorg. Med. Chem. Lett. 14(20), 5127-5131 (2004).
106. Li Y, Sun SJ, Guo QJ et al. In vitro interaction between azoles and cyclosporin A against clinical isolates of Candida albicans determined by the chequerboard method and timekill curves. J. Antimicrob. Chemother. 61(3), 577-585 (2008).
107. Holmes AR, Keniya MV, Ivnitski-Steele I et al. The monoamine oxidase A inhibitor clorgyline is a broadspectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. Antimicrob. Agents Chemother. 56(3), 1508-1515 (2012).
108. Lee KK, Maccallum DM, Jacobsen MD et al. Elevated cell wall chitin in Candida albicans confers echinocandin resistance in vivo. Antimicrob. Agents Chemother. 56(1), 208-217 (2012).
109. Douglas CM, Dippolito JA, Shei GJ et al. Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob. Agents Chemother. 41(11), 2471-2479 (1997).
110. Arellano M, Duran A, Perez P. Rho 1 GTPase activates the (1-3)beta-D-glucan synthase and is involved in Schizosaccharomyces pombe morphogenesis. EMBO J. 15(17), 4584-4591 (1996).
111. Beaulieu D, Tang J, Yan SB, Vessels JM, Radding JA, Parr TR Jr. Characterization and cilofungin inhibition of solubilized Aspergillus fumigatus (1,3)-beta-D-glucan synthase. Antimicrob. Agents Chemother. 38(5), 937-944 (1994).
112. Bartizal K, Abruzzo G, Trainor C et al. In vitro antifungal activities and in vivo efficacies of 1,3-beta-D-glucan synthesis inhibitors L-671,329, L-646,991, tetrahydroechinocandin B, and L-687,781, a papulacandin. Antimicrob. Agents Chemother. 36(8), 1648-1657 (1992).
113. Pelaez F, Cabello A, Platas G et al. The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Syst. Appl. Microbiol. 23(3), 333-343 (2000).
114. Kitamura A, Someya K, Hata M, Nakajima R, Takemura M. Discovery of a small-molecule inhibitor of {beta}-1,6-glucan synthesis. Antimicrob. Agents Chemother. 53(2), 670-677 (2009).
115. Sandovsky-Losica H, Shwartzman R, Lahat Y, Segal E. Antifungal activity against Candida albicans of nikkomycin Z in combination with caspofungin, voriconazole or amphotericin B. J. Antimicrob. Chemother. 62(3), 635-637 (2008).
116. Steinbach WJ, Cramer RA Jr, Perfect BZ et al. Calcineurin inhibition or mutation enhances cell wall inhibitors against Aspergillus fumigatus. Antimicrob. Agents Chemother. 51(8), 2979-2981 (2007).
117. Stevens DA. Drug interaction studies of a glucan synthase inhibitor (LY 303366) and a chitin synthase inhibitor (Nikkomycin Z) for inhibition and killing of fungal pathogens. Antimicrob. Agents Chemother. 44(9), 2547-2548 (2000).
118. Ganesan LT, Manavathu EK, Cutright JL, Alangaden GJ, Chandrasekar PH. In-vitro activity of nikkomycin Z alone and in combination with polyenes, triazoles or echinocandins against Aspergillus fumigatus. Clin. Microbiol. Infect. 10(11), 961-966 (2004).
119. Hector RF. Compounds active against cell walls of medically important fungi. Clin. Microbiol. Rev. 6(1), 1-21 (1993).
120. Becker JM, Covert NL, Shenbagamurthi P, Steinfeld AS, Naider F. Polyoxin D inhibits growth of zoopathogenic fungi. Antimicrob. Agents Chemother. 23(6), 926-929 (1983).
121. Mclellan CA, Whitesell L, King OD, Lancaster AK, Mazitschek R, Lindquist S. Inhibiting GPI anchor biosynthesis in fungi stresses the endoplasmic reticulum and enhances immunogenicity. ACS Chem. Biol. 7(9), 1520-1528 (2012).
122. Hata K, Horii T, Miyazaki M et al. Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis. Antimicrob. Agents Chemother. 55(10), 4543-4551 (2011).
123. Cowen LE. The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat. Rev. Microbiol. 6(3), 187-198 (2008).
124. Robbins N, Uppuluri P, Nett J et al. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog. 7(9), e1002257 (2011).
125. Kontoyiannis DP, Lewis RE, Osherov N, Albert ND, May GS. Combination of caspofungin with inhibitors of the calcineurin pathway attenuates growth in vitro in Aspergillus species. J. Antimicrob. Chemother. 51(2), 313-316 (2003).
126. Lamoth F, Juvvadi PR, Gehrke C, Steinbach WJ. In vitro activity of calcineurin and heat shock protein 90 inhibitors against Aspergillus fumigatus azole-and echinocandinresistant strains. Antimicrob. Agents Chemother. 57(2), 1035-1039 (2013).
127. Zhang J, Liu W, Tan J, Sun Y, Wan Z, Li R. Antifungal activity of geldanamycin alone or in combination with fluconazole against Candida species. Mycopathologia 175(3-4), 273-279 (2013).
128. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin. Infect. Dis. 27(3), 603-618 (1998).
129. Falci DR, Da Rosa FB, Pasqualotto AC. Comparison of nephrotoxicity associated to different lipid formulations of amphotericin B: a real-life study. Mycoses 58(2), 104-112 (2015).
130. Moreno-Rodriguez AC, Torrado-Duran S, Molero G, Garcia-Rodriguez JJ, Torrado-Santiago S. Efficacy and toxicity evaluation of new amphotericin B micelle systems for brain fungal infections. Int. J. Pharm. 494(1), 17-22 (2015).
131. Chaudhari MB, Desai PP, Patel PA, Patravale VB. Solid lipid nanoparticles of amphotericin B (AmbiOnp): in vitro and in vivo assessment towards safe and effective oral treatment module. Drug Deliv. Transl. Res. 6(4), 354-364 (2015) (Epub ahead of print).
132. Mathe L, Van Dijck P. Recent insights into Candida albicans biofilm resistance mechanisms. Curr. Genet. 59(4), 251-264 (2013).
133. Ruiz HK, Serrano DR, Dea-Ayuela MA et al. New amphotericin B-gamma cyclodextrin formulation for topical use with synergistic activity against diverse fungal species and Leishmania spp. Int. J. Pharm. 473(1-2), 148-157 (2014).
134. Tada R, Latge JP, Aimanianda V. Undressing the fungal cell wall/cell membrane-the antifungal drug targets. Curr. Pharm. Des. 19(20), 3738-3747 (2013).
135. Beauvais A, Latge JP. Membrane and cell wall targets in Aspergillus fumigatus. Drug Resist. Updat. 4(1), 38-49 (2001).
136. She XD, Khamooshi K, Gao Y et al. Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis. Cell. Microbiol. 17(9), 1350-1364 (2015).
137. Latge JP, Mouyna I, Tekaia F, Beauvais A, Debeaupuis JP, Nierman W. Specific molecular features in the organization and biosynthesis of the cell wall of Aspergillus fumigatus. Med. Mycol. 43, S15-S22 (2005).
138. Nierman WC, Pain A, Anderson MJ et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438(7071), 1151-1156 (2005).
139. Thrane C, Kaufmann U, Stummann BM, Olsson S. Activation of caspase-like activity and poly (ADP-ribose) polymerase degradation during sporulation in Aspergillus nidulans. Fungal Genet. Biol. 41(3), 361-368 (2004).
140. Leger T, Garcia C, Ounissi M, Lelandais G, Camadro JM. The metacaspase (Mca1p) has a dual role in farnesol-induced apoptosis in Candida albicans. Mol. Cell. Proteomics 14(1), 93-108 (2015).
141. Phillips AJ, Crowe JD, Ramsdale M. Ras pathway signaling accelerates programmed cell death in the pathogenic fungus Candida albicans. Proc. Natl Acad. Sci. USA 103(3), 726-731 (2006).
142. Ramsdale M. Programmed cell death in pathogenic fungi. Biochim. Biophys. Acta 1783(7), 1369-1380 (2008).
143. Martinez JL, Baquero F, Andersson Di. Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics. Curr. Opin. Pharmacol. 11(5), 439-445 (2011).
144. Andersson Di, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat. Rev. Microbiol. 8(4), 260-271 (2010).
145. Vincent BM, Lancaster AK, Scherz-Shouval R, Whitesell L, Lindquist S. Fitness trade-offs restrict the evolution of resistance to amphotericin B. PLoS Biol. 11(10), e1001692 (2013).
146. Imamovic L, Sommer MOA. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. Sci. Transl. Med. 5(204), 204ra132 (2013).
147. Rodriguez De Evgrafov M, Gumpert H, Munck C, Thomsen TT, Sommer MO. Collateral resistance and sensitivity modulate evolution of high-level resistance to drug combination treatment in Staphylococcus aureus. Mol. Biol. Evol. 32(5), 1175-1185 (2015).
148. Pal C, Papp B, Lazar V. Collateral sensitivity of antibioticresistant microbes. Trends Microbiol. 23(7), 401-407 (2015).
149. Lazar V, Pal Singh G, Spohn R et al. Bacterial evolution of antibiotic hypersensitivity. Mol. Syst. Biol. 9, 700 (2013).
150. Rank GH, Bech-Hansen NT. Single nuclear gene inherited cross resistance and collateral sensitivity to 17 inhibitors of mitochondrial function in S. cerevisiae. Mol. Gen. Genet. 126(2), 93-102 (1973).
151. Kilpatrick DC. Consensus statement on the future of mannan-binding lectin (MBL)-replacement therapy. Biochem. Soc. Trans. 31(Pt 4), 776 (2003).
152. Matthews RC, Rigg G, Hodgetts S et al. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob. Agents Chemother. 47(7), 2208-2216 (2003).
153. Larsen RA, Pappas PG, Perfect J et al. Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis. Antimicrob. Agents Chemother. 49(3), 952-958 (2005).