Chapter 24 : Insights in Antifungal Drug Discovery

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This chapter is divided into two sections. The first section focuses on clinical perspectives, especially of global candidiasis. The second section discusses antifungal drug discovery by offering two different but interacting approaches: traditional, or classical, and genomic. A large study was recently published on a 10.5-year surveillance of susceptibility of species to fluconazole and voriconazole. This study reported a slight trend toward an increasing resistance, in some regions, of NAC species like and . In human immunodeficiency virus (HIV)/AIDS patients especially, mucosal candidiasis, or oropharyngeal candidiasis (OPC), remains one of the most common types of infection throughout the world, but especially in both adult and pediatric age groups in developing countries. Information on the incidence of vulvovaginal candidiasis (VVC) is incomplete as it is not reportable. However, the estimate is that VVC caused by species affects about 70 to 75% of young women of childbearing age (most frequent); 40 to 50% of these individuals will have a recurrence, and 5 to 8% will develop recurrent VVC, defined as four or more episodes per year. Systemic candidiasis and bloodstream infections (BSI) also qualify as global infectious diseases. An increased incidence of invasive candidiasis (IC), aspergillosis, and zygomycosis has been reported in tertiary care facilities in India. The currently used echinocandins (caspofungin, micafungin, and anidulafungin) are still relatively new, and studies relating to their in vivo efficacy are ongoing.

Citation: Gay-Andrieu F, May J, Li D, Sun N, Chen H, Calderone R, Alex D. 2012. Insights in Antifungal Drug Discovery, p 387-401. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch24
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The two pathways to antifungal drug discovery. The traditional, or classical, pathway starts with compound libraries that screen a panel of fungal species. Compounds are selected as fungicidal or fungistatic, optimized for activity, and tested for in vitro toxicity, and the best lead optimized compounds are selected. Genomic approaches start with deletion sets of mutants that can provide full coverage of the genome or partial sets (as for example, growth essential genes). The deletion sets are referred to as HIP or HOP (from HI profiling or homozygous deletion profiling, respectively), reflecting the nature of the set of mutants. Mutants of genes of interest are screened against compound libraries to identify hit compounds (left-pointing diagonal arrow). Or, compounds identified by classical methods are used against sets of mutants to identify the genetic target(s) (right-pointing diagonal arrow). MFC, minimal fungicidal concentration. doi:10.1128/9781555817176.ch24.f1

Citation: Gay-Andrieu F, May J, Li D, Sun N, Chen H, Calderone R, Alex D. 2012. Insights in Antifungal Drug Discovery, p 387-401. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch24
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Image of FIGURE 2

Integration of approaches, including macromolecular synthesis inhibition, microarray (MA), deletion sets (HI profiling [HIP] and homozygous deletion profiling [HOP]), and overexpression screens (OE) to identify targets of new drugs. The genes that belong to common areas in the diagram indicate the probable target(s) of a specific compound. The asterisk indicates that genetic mutants were identified from various screens. doi:10.1128/9781555817176.ch24.f2

Citation: Gay-Andrieu F, May J, Li D, Sun N, Chen H, Calderone R, Alex D. 2012. Insights in Antifungal Drug Discovery, p 387-401. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch24
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Image of FIGURE 3

The use of interaction profiles in determining active scaffolds and drug targets. A specific phenotypic interaction between gene “g” and compound “c” is used as the basis for this interaction profile. Compounds that have high coinhibition scores with compound c and other compounds that have the same phenotypic interaction with gene g are compared for structural relatedness to identify active scaffolds or possible target sites. Similarly, genes that have high cofitness scores with gene g and other genes that have the same phenotypic interaction with compound c are compared to look for functional relatedness to identify target genes or pathways. Also, the interaction between compounds with high coinhibition scores with compound c and gene g is evaluated. Similarly, the interaction between genes that have high cofitness scores with gene g and compound c can be determined (dotted arrows). doi:10.1128/9781555817176.ch24.f3

Citation: Gay-Andrieu F, May J, Li D, Sun N, Chen H, Calderone R, Alex D. 2012. Insights in Antifungal Drug Discovery, p 387-401. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch24
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1. Ameen, M., and, R. Arenas. 2009. Developments in the management of mycetomas. Clin. Exp. Dermatol. 34: 17.
2. Arikan, S., and, J. H. Rex. 2001. Nystatin LF (Aronex/Abbott). Curr. Opin. Investig. Drugs 2: 488495.
3. Arita, A.,, X. Zhou,, T. P. Ellen,, X. Liu,, J. Bai,, J. P. Rooney,, A. Kurtz,, C. B. Klein,, W. Dai,, T. J. Begley, and, M. Costa. 2009. A genome-wide deletion mutant screen identifies pathways affected by nickel sulfate in Saccharomyces cerevisiae. BMC Genomics 10: 524.
4. Baetz, K.,, L. McHardy,, K. Gable,, T. Tarling,, D. Reberioux,, J. Bryan,, R. J. Andersen,, T. Dunn,, P. Hieter, and, M. Roberge. 2004. Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action. Proc. Natl. Acad. Sci. USA 101: 45254530.
5. Batova, M.,, V. Klobucnikova,, Z. Oblasova,, J. Gregan,, P. Zahradnik,, I. Hapala,, J. Subik, and, C. Schuller. 2010. Chemogenomic and transcriptome analysis identifies mode of action of the chemosensitizing agent CTBT (7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine). BMC Genomics 11: 153.
6. Bennett, J. E. 2009. The changing face of febrile neutropenia—from monotherapy to moulds to mucositis. Management of mycoses in neutropenic patients: a brief history, 1960–2008. J. Antimicrob. Chemother. 63 (Suppl. 1): i23i26.
7. Blignaut, E. 2007. Oral candidiasis and oral yeast carriage among institutionalised South African paediatric HIV/ AIDS patients. Mycopathologia 163: 6773.
8. Boechk, M., and, K. Marr. 2002. Infection in hematopoietic stem cell transplantation, p. 527571. In R. H. Rubin and, L. S. Young (ed.), Clinical Approach to Infection in the Compromised Host. Kluwer Academic/Plenum, New York, NY.
9. Bonifaz, A.,, D. Vazquez-Gonzalez, and, A. M. Perusquia-Ortiz. 2010. Subcutaneous mycoses: chromoblastomycosis, sporotrichosis and mycetoma. J. Dtsch. Dermatol. Ges. 8: 619627; quiz, 628.
10. Boucher, H. W.,, G. H. Talbot,, J. S. Bradley,, J. E. Edwards,, D. Gilbert,, L. B. Rice,, M. Scheld,, B. Spellberg, and, J. Bartlett. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48: 112.
11. Bougnoux, M. E.,, G. Kac,, P. Aegerter,, C. d’Enfert,, J. Y. Fagon, and, CandiRea Study Group. 2008. Candidemia and candiduria in critically ill patients admitted to intensive care units in France: incidence, molecular diversity, management and outcome. Intensive Care Med. 34: 292299.
12. Bredel, M., and, E. Jacoby. 2004. Chemogenomics: an emerging strategy for rapid target and drug discovery. Nat. Rev. Genet. 5: 262275.
13. Bromuro, C.,, M. Romano,, P. Chiani,, F. Berti,, M. Tontini,, D. Proietti,, E. Mori,, A. Torosantucci,, P. Costantino,, R. Rappuoli, and, A. Cassone. 2010. Beta-glucan-CRM197 conjugates as candidates antifungal vaccines. Vaccine 28: 26152623.
14. Cabib, E. 1991. Differential inhibition of chitin synthetases 1 and 2 from Saccharomyces cerevisiae by polyoxin D and nikkomycins. Antimicrob. Agents Chemother. 35: 170173.
15. Cagnoni, P. J.,, T. J. Walsh,, M. M. Prendergast,, D. Bodensteiner,, S. Hiemenz,, R. N. Greenberg,, C. A. Arndt,, M. Schuster,, N. Seibel,, V. Yeldandi, and, K. B. Tong. 2000. Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. J. Clin. Oncol. 18: 24762483.
16. Canton, E.,, J. Peman,, A. Valentin,, A. Espinel-Ingroff, and, M. Gobernado. 2009. In vitro activities of echinocandins against Candida krusei determined by three methods: MIC and minimal fungicidal concentration measurements and time-kill studies. Antimicrob. Agents Chemother. 53: 31083111.
17. Caston-Osorio, J. J.,, A. Rivero, and, J. Torre-Cisneros. 2008. Epidemiology of invasive fungal infection. Int. J. Antimicrob. Agents 32 (Suppl. 2): S103S109.
18. Cegelski, L.,, G. R. Marshall,, G. R. Eldridge, and, S. J. Hultgren. 2008. The biology and future prospects of anti-virulence therapies. Nat. Rev. Microbiol. 6: 1727.
19. Chakrabarti, A.,, S. S. Chatterjee, and, M. R. Shivaprakash. 2008. Overview of opportunistic fungal infections in India. Nippon Ishinkin Gakkai Zasshi 49: 165172.
20. Chakraborty, N.,, A. Mukherjee,, S. Santra,, R. N. Sarkar,, D. Banerjee,, S. K. Guha,, S. Chakraborty, and, S. K. Bhattacharyya. 2008. Current trends of opportunistic infections among HIV-seropositive patients from Eastern India. Jpn. J. Infect. Dis. 61: 4953.
21. Delmas, G.,, S. Park,, Z. W. Chen,, F. Tan,, R. Kashiwazaki,, L. Zarif, and, D. S. Perlin. 2002. Efficacy of orally delivered cochleates containing amphotericin B in a murine model of aspergillosis. Antimicrob. Agents Chemother. 46: 27042707.
22. De Pauw, B.,, T. J. Walsh,, J. P. Donnelly,, D. A. Stevens,, J. E. Edwards,, T. Calandra,, P. G. Pappas,, J. Maertens,, O. Lortholary,, C. A. Kauffman,, D. W. Denning,, T. F. Patterson,, G. Maschmeyer,, J. Bille,, W. E. Dismukes,, R. Herbrecht,, W. W. Hope,, C. C. Kibbler,, B. J. Kullberg,, K. A. Marr,, P. Munoz,, F. C. Odds,, J. R. Perfect,, A. Restrepo,, M. Ruhnke,, B. H. Segal,, J. D. Sobel,, T. C. Sorrell,, C. Viscoli,, J. R. Wingard,, T. Zaoutis,, J. E. Bennett, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group, and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. 2008. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin. Infect. Dis. 46: 18131821.
23. Dominguez, J. M., and, J. J. Martin. 1998. Identification of elongation factor 2 as the essential protein targeted by sordarins in Candida albicans. Antimicrob. Agents Chemother. 42: 22792283.
24. Drewry, D. H., and, S. S. Young. 1999. Approaches to the design of combinatorial libraries. Chemom. Intell. Lab. Syst. 48: 120.
25. Espinel-Ingroff, A. 2009. Novel antifungal agents, targets or therapeutic strategies for the treatment of invasive fungal diseases: a review of the literature (2005–2009). Rev. Iberoam. Micol. 26: 1522.
26. Fidel, P. L., Jr. 2006. Candida-host interactions in HIV disease: relationships in oropharyngeal candidiasis. Adv. Dent. Res. 19: 8084.
27. Fricker-Hidalgo, H.,, B. Lebeau,, H. Pelloux, and, R. Grillot. 2004. Use of the BACTEC 9240 System with Mycosis-IC/F blood culture bottles for detection of fungemia. J. Clin. Microbiol. 42: 18551856. (Author’s reply, 42: 18551856.)
28. Gagne, J. J., and, N. I. Goldfarb. 2007. Candidemia in the in-patient setting: treatment options and economics. Expert Opin. Pharmacother. 8: 16431650.
29. Garcia-Effron, G.,, S. K. Katiyar,, S. Park,, T. D. Edlind, and, D. S. Perlin. 2008. 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: 23052312.
30. Gavalda, J.,, O. Len,, R. San Juan,, J. M. Aguado,, J. Fortun,, C. Lumbreras,, A. Moreno,, P. Munoz,, M. Blanes,, A. Ramos,, G. Rufi,, M. Gurgui,, J. Torre-Cisneros,, M. Montejo,, M. Cuenca-Estrella,, J. L. Rodriguez-Tudela,, A. Pahissa, and RESITRA (Spanish Network for Research on Infection in Transplantation). 2005. Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study. Clin. Infect. Dis. 41: 5259.
31. Ghannoum, M. A.,, H. G. Kim, and, L. Long. 2007. Efficacy of aminocandin in the treatment of immunocompetent mice with haematogenously disseminated fluconazole-resistant candidiasis. J. Antimicrob. Chemother. 59: 556559.
32. Giaever, G.,, A. M. Chu,, L. Ni,, C. Connelly,, L. Riles,, S. Veronneau,, S. Dow,, A. Lucau-Danila,, K. Anderson,, B. Andre,, A. P. Arkin,, A. Astromoff,, M. El-Bakkoury,, R. Bangham,, R. Benito,, S. Brachat,, S. Campanaro,, M. Curtiss,, K. Davis,, A. Deutschbauer,, K. D. Entian,, P. Flaherty,, F. Foury,, D. J. Garfinkel,, M. Gerstein,, D. Gotte,, U. Guldener,, J. H. Hegemann,, S. Hempel,, Z. Herman,, D. F. Jaramillo,, D. E. Kelly,, S. L. Kelly,, P. Kotter,, D. LaBonte,, D. C. Lamb,, N. Lan,, H. Liang,, H. Liao,, L. Liu,, C. Luo,, M. Lussier,, R. Mao,, P. Menard,, S. L. Ooi,, J. L. Revuelta,, C. J. Roberts,, M. Rose,, P. Ross-Macdonald,, B. Scherens,, G. Schimmack,, B. Shafer,, D. D. Shoemaker,, S. Sookhai-Mahadeo,, R. K. Storms,, J. N. Strathern,, G. Valle,, M. Voet,, G. Volckaert,, C. Y. Wang,, T. R. Ward,, J. Wilhelmy,, E. A. Winzeler,, Y. Yang,, G. Yen,, E. Youngman,, K. Yu,, H. Bussey,, J. D. Boeke,, M. Snyder,, P. Philippsen,, R. W. Davis, and, M. Johnston. 2002. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418: 387391.
33. Giaever, G.,, P. Flaherty,, J. Kumm,, M. Proctor,, C. Nislow,, D. F. Jaramillo,, A. M. Chu,, M. I. Jordan,, A. P. Arkin, and, R. W. Davis. 2004. Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. Proc. Natl. Acad. Sci. USA 101: 793798.
34. Groll, A. H.,, P. M. Shah,, C. Mentzel,, M. Schneider,, G. Just-Nuebling, and, K. Huebner. 1996. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J. Infect. 33: 2332.
35. Guillon, R.,, F. Giraud,, C. Loge,, M. Le Borgne,, C. Picot,, F. Pagniez, and, P. Le Pape. 2009. Design of new antifungal agents: synthesis and evaluation of 1-[(1H-indol-5-ylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl) propan-2- ols. Bioorg. Med. Chem. Lett. 19: 58335836.
36. Guillon, R.,, C. Loge,, F. Pagniez,, V. Ferchaud-Roucher,, M. Duflos,, C. Picot, and, P. L. Pape. 2010. Synthesis and in vitro antifungal evaluation of 2-(2,4-difluorophenyl)-1--[(1H-indol-3-ylmethyl)methylamino]-3-(1H-1,2,4-tr iazol-1-yl)propan-2-ols. J. Enzyme Inhib. Med. Chem. 26: 261269.
37. Hachem, R.,, H. Hanna,, D. Kontoyiannis,, Y. Jiang, and, I. Raad. 2008. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer 112: 24932499.
38. Hamza, O. J.,, M. I. Matee,, M. J. Moshi,, E. N. Simon,, F. Mugusi,, F. H. Mikx,, W. H. Helderman,, A. J. Rijs,, A. J. van der Ven, and, P. E. Verweij. 2008. Species distribution and in vitro antifungal susceptibility of oral yeast isolates from Tanzanian HIV-infected patients with primary and recurrent oropharyngeal candidiasis. BMC Microbiol. 8: 135.
39. Hanadate, T.,, M. Tomishima,, N. Shiraishi,, D. Tanabe,, H. Morikawa,, D. Barrett,, S. Matsumoto,, K. Ohtomo, and, K. Maki. 2009. FR290581, a novel sordarin derivative: synthesis and antifungal activity. Bioorg. Med. Chem. Lett. 19: 14651468.
40. Harbarth, S.,, C. Ruef,, P. Francioli,, A. Widmer, and, D. Pittet. 1999. Nosocomial infections in Swiss university hospitals: a multi-centre survey and review of the published experience. Swiss-Noso Network. Schweiz. Med. Wochenschr. 129: 15211528.
41. Hasenoehrl, A.,, T. Galic,, G. Ergovic,, N. Marsic,, M. Skerlev,, J. Mittendorf,, U. Geschke,, A. Schmidt, and, W. Schoenfeld. 2006. In vitro activity and in vivo efficacy of icofungipen (PLD-118), a novel oral antifungal agent, against the pathogenic yeast Candida albicans. Antimicrob. Agents Chemother. 50: 30113018.
42. Hector, R. F.,, B. L. Zimmer, and, D. Pappagianis. 1990. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. Antimicrob. Agents Chemother. 34: 587593.
43. Hiemenz, J. W., and, T. J. Walsh. 1996. Lipid formulations of amphotericin B: recent progress and future directions. Clin. Infect. Dis. 22 (Suppl. 2): S133S144.
44. Hillenmeyer, M. E.,, E. Fung,, J. Wildenhain,, S. E. Pierce,, S. Hoon,, W. Lee,, M. Proctor,, R. P. St. Onge,, M. Tyers,, D. Koller,, R. B. Altman,, R. W. Davis,, C. Nislow, and, G. Giaever. 2008. The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320: 362365.
45. Hodgetts, S.,, L. Nooney,, R. Al-Akeel,, A. Curry,, S. Awad,, R. Matthews, and, J. Burnie. 2008. Efungumab and caspofungin: pre-clinical data supporting synergy. J. Antimicrob. Chemother. 61: 11321139.
46. Horn, D. L.,, D. Neofytos,, E. J. Anaissie,, J. A. Fishman,, W. J. Steinbach,, A. J. Olyaei,, K. A. Marr,, M. A. Pfaller,, C. H. Chang, and, K. M. Webster. 2009. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin. Infect. Dis. 48: 16951703.
47. Ibrahim, A. S.,, B. J. Spellberg,, V. Avanesian,, Y. Fu, and, J. E. Edwards, Jr. 2006. The anti- Candida vaccine based on the recombinant N-terminal domain of Als1p is broadly active against disseminated candidiasis. Infect. Immun. 74: 30393041.
48. Infectious Diseases Society of America. 2010. The 10 × ‘20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin. Infect. Dis. 50: 10811083.
49. Jabra-Rizk, M. A.,, W. A. Falkler, Jr.,, C. O. Enwonwu,, D. I. Onwujekwe, Jr.,, W. G. Merz, and, T. F. Meiller. 2001. Prevalence of yeast among children in Nigeria and the United States. Oral Microbiol. Immunol. 16: 383385.
50. Jiang, B.,, D. Xu,, J. Allocco,, C. Parish,, J. Davison,, K. Veil-lette,, S. Sillaots,, W. Hu,, R. Rodriguez-Suarez,, S. Trosok,, L. Zhang,, Y. Li,, F. Rahkhoodaee,, T. Ransom,, N. Martel,, H. Wang,, D. Gauvin,, J. Wiltsie,, D. Wisniewski,, S. Sa-lowe,, J. N. Kahn,, M. J. Hsu,, R. Giacobbe,, G. Abruzzo,, A. Flattery,, C. Gill,, P. Youngman,, K. Wilson,, G. Bills,, G. Platas,, F. Pelaez,, M. T. Diez,, S. Kauffman,, J. Becker,, G. Harris,, P. Liberator, and, T. Roemer. 2008. PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products. Chem. Biol. 15: 363374.
51. Jung, S. H.,, D. H. Lim,, S. H. Jung,, J. E. Lee,, K. S. Jeong,, H. Seong, and, B. C. Shin. 2009. Amphotericin B-entrapping lipid nanoparticles and their in vitro and in vivo characteristics. Eur. J. Pharm. Sci. 37: 313320.
52. Justice, M. C.,, M. J. Hsu,, B. Tse,, T. Ku,, J. Balkovec,, D. Schmatz, and, J. Nielsen. 1998. Elongation factor 2 as a novel target for selective inhibition of fungal protein synthesis. J. Biol. Chem. 273: 31483151.
53. Kakeya, H.,, Y. Miyazaki,, H. Senda,, T. Kobayashi,, M. Seki,, K. Izumikawa,, K. Yanagihara,, Y. Yamamoto,, T. Tashiro, and, S. Kohno. 2008. Efficacy of SPK-843, a novel polyene antifungal, in comparison with amphotericin B, liposomal amphotericin B, and micafungin against murine pulmonary aspergillosis. Antimicrob. Agents Chemother. 52: 18681870.
54. Kamai, Y.,, M. Kakuta,, T. Shibayama,, T. Fukuoka, and, S. Kuwahara. 2005. Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice. Anti-microb. Agents Chemother. 49: 5256.
55. Kang, T. H.,, E. I. Hwang,, B. S. Yun,, K. D. Park,, B. M. Kwon,, C. S. Shin, and, S. U. Kim. 2007. Inhibition of chitin synthases and antifungal activities by 2‵-benzoyloxycinnamaldehyde from Pleuropterus ciliinervis and its derivatives. Biol. Pharm. Bull. 30: 598602.
56. Kang, T. H.,, E. I. Hwang,, B. S. Yun,, C. S. Shin, and, S. U. Kim. 2008. Chitin synthase 2 inhibitory activity of O-methyl pisiferic acid and 8,20-dihydroxy-9( 11),13-abietadien-12-one, isolated from Chamaecyparis pisifera. Biol. Pharm. Bull. 31: 755759.
57. Kitamura, A.,, K. Someya,, M. Hata,, R. Nakajima, and, M. Takemura. 2009. Discovery of a small-molecule inhibitor of β-1,6-glucan synthesis. Antimicrob. Agents Chemother. 53: 670677.
58. Knaus, W. A.,, D. P. Wagner,, E. A. Draper,, J. E. Zimmerman,, M. Bergner,, P. G. Bastos,, C. A. Sirio,, D. J. Murphy,, T. Lotring, and, A. Damiano. 1991. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 100: 16191636.
59. Kontoyiannis, D. P.,, K. A. Marr,, B. J. Park,, B. D. Alexander,, E. J. Anaissie,, T. J. Walsh,, J. Ito,, D. R. Andes,, J. W. Baddley,, J. M. Brown,, L. M. Brumble,, A. G. Freifeld,, S. Hadley,, L. A. Herwaldt,, C. A. Kauffman,, K. Knapp,, G. M. Lyon,, V. A. Morrison,, G. Papanicolaou,, T. F. Patterson,, T. M. Perl,, M. G. Schuster,, R. Walker,, K. A. Wannemuehler,, J. R. Wingard,, T. M. Chiller, and, P. G. Pappas. 2010. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin. Infect. Dis. 50: 10911100.
60. Krcmery, V., and, A. J. Barnes. 2002. Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J. Hosp. Infect. 50: 243260.
61. Lass-Florl, C. 2009. The changing face of epidemiology of invasive fungal disease in Europe. Mycoses 52: 197205.
62. Lehrnbecher, T.,, C. Frank,, K. Engels,, S. Kriener,, A. H. Groll, and, D. Schwabe. 2010. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J. Infect. 61: 259265.
63. Lewis, R. E. 2007. Pharmacodynamic implications for use of antifungal agents. Curr. Opin. Pharmacol. 7: 491497.
64. Li, D.,, O. A. Agrellos, and, R. Calderone. 2010. Histidine kinases keep fungi safe and vigorous. Curr. Opin. Microbiol. 13: 424430.
65. Li, J. W., and, J. C. Vederas. 2009. Drug discovery and natural products: end of an era or an endless frontier? Science 325: 161165.
66. Liu, T. T.,, R. E. Lee,, K. S. Barker,, R. E. Lee,, L. Wei,, R. Homayouni, and, P. D. Rogers. 2005. Genome-wide expression profiling of the response to azole, polyene, echinocandin, and pyrimidine antifungal agents in Candida albicans. Antimicrob. Agents Chemother. 49: 22262236.
67. Lortholary, O.,, D. W. Denning, and, B. Dupont. 1999. Endemic mycoses: a treatment update. J. Antimicrob. Chemother. 43: 321331.
68. Lortholary, O.,, M. Desnos-Ollivier,, K. Sitbon,, A. Fontanet,, S. Bretagne,, F. Dromer, and the French Mycosis Study Group. 2011. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob. Agents Chemother. 55: 532538.
69. Micol, R.,, A. Tajahmady,, O. Lortholary,, S. Balkan,, C. Quillet,, J. P. Dousset,, H. Chanroeun,, Y. Madec,, A. Fontanet, and, Y. Yazdanpanah. 2010. Cost-effectiveness of primary prophylaxis of AIDS associated cryptococcosis in Cambodia. PLoS One 5: e13856.
70. Miller, L. G.,, R. A. Hajjeh, and, J. E. Edwards, Jr. 2001. Estimating the cost of nosocomial candidemia in the United States. Clin. Infect. Dis. 32: 1110.
71. Mitsuyama, J.,, N. Nomura,, K. Hashimoto,, E. Yamada,, H. Nishikawa,, M. Kaeriyama,, A. Kimura,, Y. Todo, and, H. Narita. 2008. In vitro and in vivo antifungal activities of T-2307, a novel arylamidine. Antimicrob. Agents Chemother. 52: 13181324.
72. Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65: 5563.
73. Nadagir, S. D.,, S. K. Chunchanur,, L. H. Halesh,, K. Yasmeen,, M. R. Chandrasekhar, and, B. S. Patil. 2008. Significance of isolation and drug susceptibility testing of non- Candida albicans species causing oropharyngeal candidiasis in HIV patients. Southeast Asian J. Trop. Med. Public Health 39: 492495.
74. Nakamata, K.,, T. Kurita,, M. S. Bhuiyan,, K. Sato,, Y. Noda, and, K. Yoda. 2007. KEG1/YFR042w encodes a novel Kre6-binding endoplasmic reticulum membrane protein responsible for beta-1,6-glucan synthesis in Saccharomyces cerevisiae. J. Biol. Chem. 282: 3431534324.
75. Neofytos, D.,, D. Horn,, E. Anaissie,, W. Steinbach,, A. Olyaei,, J. Fishman,, M. Pfaller,, C. Chang,, K. Webster, and, K. Marr. 2009. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin. Infect. Dis. 48: 265273.
76. Niimi, M.,, N. A. Firth, and, R. D. Cannon. 2010. Antifungal drug resistance of oral fungi. Odontology 98: 1525.
77. Nishikaku, A.,, A. Melo, and, A. Colombo. 2010. Geographic trends in invasive candidiasis. Curr. Fungal Infect. 4: 210218.
78. Nomura, K.,, K. Kawasugi, and, T. Morimoto. 2006. Cost-effectiveness analysis of antifungal treatment for patients on chemotherapy. Eur. J. Cancer Care (Engl.) 15: 4450.
79. Odds, F. C.,, A. J. Brown, and, N. A. Gow. 2003. Antifungal agents: mechanisms of action. Trends Microbiol. 11: 272279.
80. Oh, J.,, E. Fung,, U. Schlecht,, R. W. Davis,, G. Giaever,, R. P. St. Onge,, A. Deutschbauer, and, C. Nislow. 2010. Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. PLoS Pathog. 6: e1001140.
81. Okome-Nkoumou, M.,, M. E. Mbounja-Loclo, and, M. Kombila. 2000. Spectrum of opportunistic infections in subjects infected with HIV at Libreville, Gabon. Sante 10: 329337. (In French.)
82. Olaechea, P. M.,, M. Palomar,, C. Leon-Gil,, F. Alvarez-Lerma,, R. Jorda,, J. Nolla-Salas,, M. A. Leon-Regidor, and EPCAN Study Group. 2004. Economic impact of Candida colonization and Candida infection in the critically ill patient. Eur. J. Clin. Microbiol. Infect. Dis. 23: 323330.
83. Ostrosky-Zeichner, L.,, A. Casadevall,, J. N. Galgiani,, F. C. Odds, and, J. H. Rex. 2010. An insight into the antifungal pipeline: selected new molecules and beyond. Nat. Rev. Drug Discov. 9: 719727.
84. Pachl, J.,, P. Svoboda,, F. Jacobs,, K. Vandewoude,, B. van der Hoven,, P. Spronk,, G. Masterson,, M. Malbrain,, M. Aoun,, J. Garbino,, J. Takala,, L. Drgona,, J. Burnie,, R. Matthews, and Mycograb Invasive Candidiasis Study Group. 2006. 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. 42: 14041413.
85. Pappas, P. G.,, B. D. Alexander,, D. R. Andes,, S. Hadley,, C. A. Kauffman,, A. Freifeld,, E. J. Anaissie,, L. M. Brumble,, L. Herwaldt,, J. Ito,, D. P. Kontoyiannis,, G. M. Lyon,, K. A. Marr,, V. A. Morrison,, B. J. Park,, T. F. Patterson,, T. M. Perl,, R. A. Oster,, M. G. Schuster,, R. Walker,, T. J. Walsh,, K. A. Wannemuehler, and, T. M. Chiller. 2010. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin. Infect. Dis. 50: 11011111.
86. Pappas, P. G.,, C. A. Kauffman,, D. Andes,, D. K. Benjamin, Jr.,, T. F. Calandra,, J. E. Edwards, Jr.,, S. G. Filler,, J. F. Fisher,, B. J. Kullberg,, L. Ostrosky-Zeichner,, A. C. Reboli,, J. H. Rex,, T. J. Walsh,, J. D. Sobel, and Infectious Diseases Society of America. 2009. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 48: 503535.
87. Parish, C. A.,, S. K. Smith,, K. Calati,, D. Zink,, K. Wilson,, T. Roemer,, B. Jiang,, D. Xu,, G. Bills,, G. Platas,, F. Pelaez,, M. T. Diez,, N. Tsou,, A. E. McKeown,, R. G. Ball,, M. A. Powles,, L. Yeung,, P. Liberator, and, G. Harris. 2008. Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation. J. Am. Chem. Soc. 130: 70607066.
88. Peman, J., and, R. Zaragoza. 2010. Current diagnostic approaches to invasive candidiasis in critical care settings. Mycoses 53: 424433.
89. Pfaller, M. A.,, L. Boyken,, R. J. Hollis,, S. A. Messer,, S. Tendolkar, and, D. J. Diekema. 2006. In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance. J. Clin. Microbiol. 44: 760763.
90. Pfaller, M. A.,, M. Castanheira,, S. A. Messer,, G. J. Moet, and, R. N. Jones. 2010. Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008–2009). Diagn. Microbiol. Infect. Dis. 68: 278283.
91. Pfaller, M. A., and, D. J. Diekema. 2007. Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20: 133163.
92. Pfaller, M. A.,, D. J. Diekema,, D. L. Gibbs,, V. A. Newell,, H. Bijie,, D. Dzierzanowska,, N. N. Klimko,, V. Letscher-Bru,, M. Lisalova,, K. Muehlethaler,, C. Rennison,, M. Zaidi, and Global Antifungal Surveillance Group. 2009. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10.5-year analysis of susceptibilities of noncandidal yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J. Clin. Microbiol. 47: 117123.
93. Pfaller, M. A.,, D. J. Diekema,, D. L. Gibbs,, V. A. Newell,, D. Ellis,, V. Tullio,, A. Rodloff,, W. Fu,, T. A. Ling, and the Global Antifungal Surveillance Group. 2010. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J. Clin. Microbiol. 48: 13661377.
94. Pfaller, M. A.,, D. J. Diekema, and International Fungal Surveillance Participant Group. 2004. Twelve years of fluconazole in clinical practice: global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida. Clin. Microbiol. Infect. 10 (Suppl. 1): 1123.
95. Pfaller, M. A.,, S. A. Messer,, N. Georgopapadakou,, L. A. Martell,, J. M. Besterman, and, D. J. Diekema. 2009. Activity of MGCD290, a Hos2 histone deacetylase inhibitor, in combination with azole antifungals against opportunistic fungal pathogens. J. Clin. Microbiol. 47: 37973804.
96. Pienaar, E. D.,, T. Young, and, H. Holmes. 2010. Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database Syst. Rev. 11: CD003940.
97. Playford, E. G.,, J. Lipman, and, T. C. Sorrell. 2010. Prophylaxis, empirical and preemptive treatment of invasive candidiasis. Curr. Opin. Crit. Care 16: 470474.
98. Prentice, H. G.,, I. M. Hann,, R. Herbrecht,, M. Aoun,, S. Kvaloy,, D. Catovsky,, C. R. Pinkerton,, S. A. Schey,, F. Jacobs,, A. Oakhill,, R. F. Stevens,, P. J. Darbyshire, and, B. E. Gibson. 1997. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br. J. Haematol. 98: 711718.
99. Qin, Z.,, J. Zhang,, B. Xu,, L. Chen,, Y. Wu,, X. Yang,, X. Shen,, S. Molin,, A. Danchin,, H. Jiang, and, D. Qu. 2006. Structure-based discovery of inhibitors of the YycG histi-dine kinase: new chemical leads to combat Staphylococcus epidermidis infections. BMC Microbiol. 6: 96.
100. Rentz, A. M.,, M. T. Halpern, and, R. Bowden. 1998. The impact of candidemia on length of hospital stay, outcome, and overall cost of illness. Clin. Infect. Dis. 27: 781788.
101. Repetto, G.,, A. del Peso, and, J. L. Zurita. 2008. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat. Protoc. 3: 11251131.
102. Rijnders, B. J.,, J. J. Cornelissen,, L. Slobbe,, M. J. Becker,, J. K. Doorduijn,, W. C. Hop,, E. J. Ruijgrok,, B. Lowenberg,, A. Vulto,, P. J. Lugtenburg, and, S. de Marie. 2008. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin. Infect. Dis. 46: 14011408.
103. Rodriguez-Suarez, R.,, D. Xu,, K. Veillette,, J. Davison,, S. Sillaots,, S. Kauffman,, W. Hu,, J. Bowman,, N. Martel,, S. Trosok,, H. Wang,, L. Zhang,, L. Y. Huang,, Y. Li,, F. Rahkhoodaee,, T. Ransom,, D. Gauvin,, C. Douglas,, P. Youngman,, J. Becker,, B. Jiang, and, T. Roemer. 2007. Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus. Chem. Biol. 14: 11631175.
104. Roemer, T.,, B. Jiang,, J. Davison,, T. Ketela,, K. Veillette,, A. Breton,, F. Tandia,, A. Linteau,, S. Sillaots,, C. Marta,, N. Martel,, S. Veronneau,, S. Lemieux,, S. Kauffman,, J. Becker,, R. Storms,, C. Boone, and, H. Bussey. 2003. Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol. Microbiol. 50: 167181.
105. Sampaio Camargo, T. Z.,, A. R. Marra,, C. V. Silva,, M. F. Cardoso,, M. D. Martino,, L. F. Camargo, and, L. Correa. 2010. Secular trends of candidemia in a tertiary care hospital. Am. J. Infect. Control 38: 546551.
106. Santangelo, R.,, P. Paderu,, G. Delmas,, Z. W. Chen,, R. Mannino,, L. Zarif, and, D. S. Perlin. 2000. Efficacy of oral cochleate-amphotericin B in a mouse model of systemic candidiasis. Antimicrob. Agents Chemother. 44: 23562360.
107. Seifert, H.,, U. Aurbach,, D. Stefanik, and, O. Cornely. 2007. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Anti-microb. Agents Chemother. 51: 18181821.
108. Smith, A. M.,, R. Ammar,, C. Nislow, and, G. Giaever. 2010. A survey of yeast genomic assays for drug and target discovery. Pharmacol. Ther. 127: 156164.
109. Sobel, J. D. 2007. Vulvovaginal candidosis. Lancet 369: 19611971.
110. Sopko, R.,, D. Huang,, N. Preston,, G. Chua,, B. Papp,, K. Kafadar,, M. Snyder,, S. G. Oliver,, M. Cyert,, T. R. Hughes,, C. Boone, and, B. Andrews. 2006. Mapping pathways and phenotypes by systematic gene overexpression. Mol. Cell 21: 319330.
111. Sorbera, L. A.,, J. Bartroli, and, J. Castaner. 2003. Alba-conazole. Drugs Future 28: 529537.
112. Spellberg, B. J.,, S. G. Filler, and, J. E. Edwards, Jr. 2006. Current treatment strategies for disseminated candidiasis. Clin. Infect. Dis. 42: 244251.
113. Spellberg, B. J.,, A. S. Ibrahim,, V. Avanesian,, Y. Fu,, C. Myers,, Q. T. Phan,, S. G. Filler,, M. R. Yeaman, and, J. E. Edwards, Jr. 2006. Efficacy of the anti- Candida rAls3p-N or rAls1p-N vaccines against disseminated and mucosal candidiasis. J. Infect. Dis. 194: 256260.
114. Tolman, J. A.,, N. P. Wiederhold,, J. T. McConville,, L. K. Najvar,, R. Bocanegra,, J. I. Peters,, J. J. Coalson,, J. R. Graybill,, T. F. Patterson, and, R. O. Williams III. 2009. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis. Antimicrob. Agents Chemother. 53: 26132615.
115. Trofa, D.,, A. Gacser, and, J. D. Nosanchuk. 2008. Candida parapsilosis, an emerging fungal pathogen. Clin. Microbiol. Rev. 21: 606625.
116. Uppuluri, P.,, J. Nett,, J. Heitman, and, D. Andes. 2008. Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms. Antimicrob. Agents Chemother. 52: 11271132.
117. van der Meer, J. W.,, F. L. van de Veerdonk,, L. A. Joosten,, B. J. Kullberg, and, M. G. Netea. 2010. Severe Candida spp. infections: new insights into natural immunity. Int. J. Antimicrob. Agents 36 (Suppl. 2): S58S62.
118. van Gool, R. 2001. The cost of treating systemic fungal infections. Drugs 61 (Suppl. 1): 4956.
119. Vogel, H. G. 2007. Assays for insulin and insulin-like metabolic activity, p. 14151416. In H. G. Vogel (ed.), Drug Discovery and Evaluation: Pharmacological Assays, 3rd ed. Springer, New York, NY.
120. Walsh, T. J.,, J. Hiemenz, and, P. A. Pizzo. 1994. Evolving risk factors for invasive fungal infections—all neutropenic patients are not the same. Clin. Infect. Dis. 18: 793798.
121. Warn, P. A.,, A. Sharp,, G. Morrissey, and, D. W. Denning. 2005. Activity of aminocandin (IP960) compared with amphotericin B and fluconazole in a neutropenic murine model of disseminated infection caused by a fluconazole-resistant strain of Candida tropicalis. J. Antimicrob. Chemother. 56: 590593.
122. Warn, P. A.,, A. Sharp,, G. Morrissey, and, D. W. Denning. 2010. Activity of aminocandin (IP960; HMR3270) compared with amphotericin B, itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus. Int. J. Anti-microb. Agents 35: 146151.
123. Weig, M., and, A. J. Brown. 2007. Genomics and the development of new diagnostics and anti- Candida drugs. Trends Microbiol. 15: 310317.
124. Wertheimer, A. I.,, T. M. Santella, and, H. J. Lauver. 2004. Successful public/private donation programs: a review of the Diflucan Partnership Program in South Africa. J. Int. Assoc. Physicians AIDS Care 3: 74–79, 84–85.
125. Widmer, F.,, L. C. Wright,, D. Obando,, R. Handke,, R. Ganendren,, D. H. Ellis, and, T. C. Sorrell. 2006. Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis. Antimicrob. Agents Chemother. 50: 414421.
126. Wilson, L. S.,, C. M. Reyes,, M. Stolpman,, J. Speckman,, K. Allen, and, J. Beney. 2002. The direct cost and incidence of systemic fungal infections. Value Health 5: 2634.
127. Xu, D.,, B. Jiang,, T. Ketela,, S. Lemieux,, K. Veillette,, N. Martel,, J. Davison,, S. Sillaots,, S. Trosok,, C. Bachewich,, H. Bussey,, P. Youngman, and, T. Roemer. 2007. Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans. PLoS Pathog. 3: e92.
128. Yamada, E.,, H. Nishikawa,, N. Nomura, and, J. Mitsuyama. 2010. T-2307 shows efficacy in a murine model of Candida glabrata infection despite in vitro trailing growth phenomena. Antimicrob. Agents Chemother. 54: 36303634.
129. Yim, N. H.,, E. I. Hwang,, B. S. Yun,, K. D. Park,, J. S. Moon,, S. H. Lee,, N. D. Sung, and, S. U. Kim. 2008. Sesquiterpene furan compound CJ-01, a novel chitin synthase 2 inhibitor from Chloranthus japonicus SIEB. Biol. Pharm. Bull. 31: 10411044.
130. Zarif, L.,, J. R. Graybill,, D. Perlin,, L. Najvar,, R. Bocanegra, and, R. J. Mannino. 2000. Antifungal activity of amphotericin B cochleates against Candida albicans infection in a mouse model. Antimicrob. Agents Chemother. 44: 14631469.
131. Zhang, X.,, P. A. Reichart, and, Y. Song. 2009. Oral manifestations of HIV/AIDS in China: a review. Oral Maxillofac. Surg. 13: 6368.
132. Zilberberg, M. D.,, M. H. Kollef,, H. Arnold,, A. Labelle,, S. T. Micek,, S. Kothari, and, A. F. Shorr. 2010. Inappropriate empiric antifungal therapy for candidemia in the ICU and hospital resource utilization: a retrospective cohort study. BMC Infect. Dis. 10: 150.

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