Skip to main content
SpringerLink
Log in

Drugs in Clinical Development for Fungal Infections

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Despite increasing rates of invasive fungal infections being reported globally, only a single antifungal drug has been approved during the last decade. Resistance, toxicity, drug interactions and restricted routes of administration remain unresolved issues. This review focuses on new antifungal compounds which are currently in various clinical phases of development. We discuss two azoles with a tetrazole moiety that allows selective activity against the fungal CYP: VT-1161 for Candida infections and VT-1129 for cryptococcal meningoencephalitis. We also discuss two glucan synthesis inhibitors: CD101, an echinocandin with an increased half-life, and SCY-078 with oral bioavailability and increased activity against echinocandin-resistant isolates. Among the polyenes, we discuss MAT023, an encochleated amphotericin B formulation that allows oral administration. Two novel classes of antifungal drugs are also described: glycosylphosphatidylinositol inhibitors, and the leading drug APX001, which disrupt the integrity of the fungal wall; and the orotomides, inhibitors of pyrimidine synthesis with the leading drug F901318. Finally, a chitin synthesis inhibitor and progress on human monoclonal antifungal antibodies are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4(165):165rv13. doi:10.1126/scitranslmed.3004404.

    Article  PubMed  Google Scholar 

  2. Vos T, Flaxman A, Naghavi M, Lozano R. Years lived with disability [YLD] for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of disease study. Lancet. 2012;380:2163–96. doi:10.1016/S0140-6736(12),61729-2.

    Article  PubMed  Google Scholar 

  3. Pfaller MA, Pappas P, Wingard J. Invasive fungal pathogens: current epidemiological trends. Clin Infect Dis. 2006;43(Supplement 1):S3–14. doi:10.1086/504490.

    Article  CAS  Google Scholar 

  4. Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis. 2016;62(3):362–8. doi:10.1093/cid/civ885.

    Article  PubMed  Google Scholar 

  5. Pfaller MA, Messer SA, Woosley LN, Jones RN, Castanheira M. Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol. 2013;51(8):2571–81. doi:10.1128/JCM.00308-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Murrell D, Bossaer JB, Carico R, Harirforoosh S, Cluck D. Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections. Int J Pharm Pract. 2017;25(1):18–30. doi:10.1111/ijpp.12302.

    Article  PubMed  Google Scholar 

  7. Miceli MH, Kauffman CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis. 2015;61(10):1558–65. doi:10.1093/cid/civ571.

    Article  CAS  PubMed  Google Scholar 

  8. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–9. doi:10.1016/S0140-6736(15)01159-9.

    Article  CAS  PubMed  Google Scholar 

  9. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR 3rd, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16(7):828–37. doi:10.1016/S1473-3099(16)00071-2.

    Article  CAS  PubMed  Google Scholar 

  10. Astellas. Astellas provides update on phase 3 study evaluating isavuconazole in patients with candidemia and other invasive Candida infections. 2015. http://newsroom.astellas.us/2015-07-30-Astellas-Provides-Update-on-Phase-3-Study-Evaluating-Isavuconazole-in-Patients-with-Candidemia-and-Other-Invasive-Candida-Infections. Accessed 24 Mar 2017.

  11. Wilson DT, Dimondi VP, Johnson SW, Jones TM, Drew RH. Role of isavuconazole in the treatment of invasive fungal infections. Ther Clin Risk Manag. 2016;12:1197–206. doi:10.2147/TCRM.S90335.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pfaller MA, Rhomberg PR, Messer SA, Jones RN, Castanheira M. Isavuconazole, micafungin, and 8 comparator antifungal agents’ susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values. Diagn Microbiol Infect Dis. 2015;82(4):303–13. doi:10.1016/j.diagmicrobio.2015.04.008.

    Article  CAS  PubMed  Google Scholar 

  13. Guinea J, Pelaez T, Recio S, Torres-Narbona M, Bouza E. In vitro antifungal activities of isavuconazole (BAL4815), voriconazole, and fluconazole against 1,007 isolates of zygomycete, Candida, Aspergillus, Fusarium, and Scedosporium species. Antimicrob Agents Chemother. 2008;52(4):1396–400. doi:10.1128/AAC.01512-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arendrup MC, Jensen RH, Meletiadis J. In vitro activity of isavuconazole and comparators against clinical isolates of the mucorales order. Antimicrob Agents Chemother. 2015;59(12):7735–42. doi:10.1128/AAC.01919-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thompson GR 3rd, Wiederhold NP. Isavuconazole: a comprehensive review of spectrum of activity of a new triazole. Mycopathologia. 2010;170(5):291–313. doi:10.1007/s11046-010-9324-3.

    Article  CAS  PubMed  Google Scholar 

  16. Moriyama B, Gordon LA, McCarthy M, Henning SA, Walsh TJ, Penzak SR. Emerging drugs and vaccines for candidemia. Mycoses. 2014;57(12):718–33. doi:10.1111/myc.12265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Viamet. Clinical trials. 2016. http://www.viamet.com/pipeline/clinical-trials.php. Accessed 24 Mar 2017.

  18. Hoekstra WJ, Garvey EP, Moore WR, Rafferty SW, Yates CM, Schotzinger RJ. Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorg Med Chem Lett. 2014;24(15):3455–8. doi:10.1016/j.bmcl.2014.05.068.

    Article  CAS  PubMed  Google Scholar 

  19. Warrilow AG, Hull CM, Parker JE, Garvey EP, Hoekstra WJ, Moore WR, et al. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob Agents Chemother. 2014;58(12):7121–7. doi:10.1128/AAC.03707-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Warrilow AG, Parker JE, Price CL, Nes WD, Garvey EP, Hoekstra WJ, et al. The investigational drug VT-1129 is a highly potent inhibitor of cryptococcus species CYP51 but only weakly inhibits the human enzyme. Antimicrob Agents Chemother. 2016;60(8):4530–8. doi:10.1128/AAC.00349-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fotherhill AW, Rinaldi MG, Hoekstra WJ. In vitro activity of two metalloenzyme inhibitors compared to caspofungin and fluconazole against a panel of 74 Candida spp. Interscience Conference on Antimicrobial Agents and Chemotherapy; Boston. 2010.

  22. Fotherhill AW, Rinaldi MG, Hoekstra WJ. The fungal CYP51 inhibitor VT-1129 and VT-1161 maintain in vitro activity against Candida albicans isolates with reduced antifungal susceptibility. Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago. 2011.

  23. Garvey EP, Hoekstra WJ, Schotzinger RJ, Sobel JD, Lilly EA, Fidel PL Jr. Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis. Antimicrob Agents Chemother. 2015;59(9):5567–73. doi:10.1128/AAC.00185-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Najvar LK, Wiederhold NP, Garvey EP, Hoekstra WJ. Efficacy of the novel fungal CYP51 inhibitor VT-1161 against invasive candidiasis caused by resistant Candida albicans. Berlin: Congress of the International Society for Human and Animal Mycology; 2012.

    Google Scholar 

  25. Gebremariam T, Wiederhold NP, Fothergill AW, et al. VT-1161 protects immunosuppressed mice from Rhizopus arrhizus var. arrhizus infection. Antimicrob Agents Chemother. 2015;59(12):7815–7. doi:10.1128/AAC.01437-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shubitz LF, Trinh HT, Galgiani JN, et al. Evaluation of VT-1161 for treatment of coccidioidomycosis in murine infection models. Antimicrob Agents Chemother. 2015;59(12):7249–54. doi:10.1128/AAC.00593-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brand S, Dehenhardt T, Nyirjesy P, Augenbraun M, Schotzinger RJ. Efficacy and safety of oral VT-1161, a novel inhibitor of fungal CYP51, in a randomized phase 2 study in patients with acute vulvovaginal candidiasis: six-month follow-up. Portland: Infectious Diseases Society for Obstetrics and Gynecology Annual Meeting; 2015.

    Google Scholar 

  28. Brand SR, Degenhart TP, Person KL, et al. Oral VT-1161 is highly effective and safe in patients with recurrent vulvovaginal candidiasis - results of REVIVE, a multicenter phase 2b study. ASM Microbe. New Orleans: Viamet Pharmaceuticals; 2017.

    Google Scholar 

  29. Elewski B, Kempers S, Bhatia N, Blauvelt A, Curelop S, Brand S et al. Efficacy and safety of VT-1161 in a randomized, double-blinded, placebo-controlled phase 2 study of four oral dosing regimens in the treatment of patients with moderate-to-severe distal-lateral subungual onychomycosis (DLSO). 4th International Summit on Nail Diseases; June 23–25, 2017; Athens, Greece. 2017.

  30. Lockhart SR, Fothergill AW, Iqbal N, et al. The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. Antimicrob Agents Chemother. 2016;60(4):2528–31. doi:10.1128/AAC.02770-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nielsen K, Vedula P, Smith KD, Meya DB, Garvey EP, Hoekstra WJ, et al. Activity of VT-1129 against Cryptococcus neoformans clinical isolates with high fluconazole MICs. Med Mycol. 2016. doi:10.1093/mmy/myw089.

    Google Scholar 

  32. Wiederhold NP, Najvar LK, Alimardanov A, Cradock J. The novel fungal Cyp51 inhibitor VT-1129 demonstrates potent in vivo activity in mice against cryptococcal meningitis with a loading/maintenance dose strategy. Copenhagen: ESCMID; 2015.

    Google Scholar 

  33. Heasley BH, Pacofsky GJ, Mamai A, Liu H, Nelson K, Coti G, et al. Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of beta-1,3-glucan synthase. Bioorg Med Chem Lett. 2012;22(22):6811–6. doi:10.1016/j.bmcl.2012.05.031.

    Article  CAS  PubMed  Google Scholar 

  34. Onishi J, Meinz M, Thompson J, Curotto J, Dreikorn S, Rosenbach M, et al. Discovery of novel antifungal (1,3)-beta-d-glucan synthase inhibitors. Antimicrob Agents Chemother. 2000;44(2):368–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pelaez F, Cabello A, Platas G, Diez MT, Gonzalez del Val A, Basilio A, 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. 2000;23(3):333–43.

    Article  CAS  PubMed  Google Scholar 

  36. Pfaller MA, Messer SA, Motyl MR, Jones RN, Castanheira M. Activity of MK-3118, a new oral glucan synthase inhibitor, tested against Candida spp. by two international methods (CLSI and EUCAST). J Antimicrob Chemother. 2013;68(4):858–63. doi:10.1093/jac/dks466.

    Article  CAS  PubMed  Google Scholar 

  37. Jimenez-Ortigosa C, Paderu P, Motyl MR, Perlin DS. Enfumafungin derivative MK-3118 shows increased in vitro potency against clinical echinocandin-resistant Candida species and Aspergillus species isolates. Antimicrob Agents Chemother. 2014;58(2):1248–51. doi:10.1128/AAC.02145-13.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Walker SS, Xu Y, Triantafyllou I, Waldman MF, Mendrick C, Brown N, et al. Discovery of a novel class of orally active antifungal beta-1,3-d-glucan synthase inhibitors. Antimicrob Agents Chemother. 2011;55(11):5099–106. doi:10.1128/AAC.00432-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lepak AJ, Marchillo K, Andes DR. Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY-078 (MK-3118), using an in vivo murine invasive candidiasis model. Antimicrob Agents Chemother. 2015;59(2):1265–72. doi:10.1128/AAC.04445-14.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lamoth F, Alexander BD. Antifungal activities of SCY-078 (MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates. Antimicrob Agents Chemother. 2015;59(7):4308–11. doi:10.1128/AAC.00234-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Roman M, Hernandez C, Blanco D, Obrycki G, Helou S. A multicentre, randomized, evaluator-blinded, active controlled study to evaluate the safety and efficacy of oral SCY-078 in subjects with moderate to severe vulvovaginal candidiasis. 27th ECCMID; Vienna, Austria. 2017.

  42. Pappas P, Pullman J, Thompson G, Powderly W, Spec A, Tobin E et al. A prospective, phase 2, multicenter, open-label, randomized, comparative study to estimate the safety, tolerability, pharmacokinetics and efficacy of oral SCY-078 vs. standard-of-care following initial intravenous echinocandin therapy in the treatment of invasive candidiasis (including candidemia) in hospitalized non-neutropenic adults (Mycoses Study Group 010) 27th ECCMID Vienna, Austria. 2017.

  43. Krishnan BR, James KD, Polowy K, Bryant BJ, Vaidya A, Smith S, et al. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J Antibiot (Tokyo). 2017;70(2):130–5. doi:10.1038/ja.2016.89.

    Article  CAS  PubMed  Google Scholar 

  44. Pfaller MA, Messer SA, Rhomberg PR, Jones RN, Castanheira M. Activity of a long-acting echinocandin, CD101, determined using CLSI and EUCAST reference methods, against Candida and Aspergillus spp., including echinocandin- and azole-resistant isolates. J Antimicrob Chemother. 2016;71(10):2868–73. doi:10.1093/jac/dkw214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ong V, Hough G, Schlosser M, Bartizal K, Balkovec JM, James KD, et al. Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin. Antimicrob Agents Chemother. 2016;60(11):6872–9. doi:10.1128/AAC.00701-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Locke JB, Almaguer AL, Zuill DE, Bartizal K. Characterization of in vitro resistance development to the novel echinocandin CD101 in Candida species. Antimicrob Agents Chemother. 2016;60(10):6100–7. doi:10.1128/AAC.00620-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao Y, Perez WB, Jimenez-Ortigosa C, Hough G, Locke JB, Ong V, et al. CD101: a novel long-acting echinocandin. Cell Microbiol. 2016;18(9):1308–16. doi:10.1111/cmi.12640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sandison T, Armas D, Lee J, Ong V. Safety and pharmacokinetics of single and multiple doses of CD101 IV: results from two phase 1 dose-escalation studies. American College of Clinical Pharmacy Annual Meeting; Hollywood, Florida. 2016

  49. Cidara. Cidara Therapeutics reports unfavorable results of phase 2 RADIANT trial of CD101 topical in VVC. Cidara Therapeutics Webpage. 2017. http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2247615. Accessed 14 Aug 2017.

  50. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73(9):919–34. doi:10.1007/s40265-013-0069-4.

    Article  CAS  PubMed  Google Scholar 

  51. Segarra I, Movshin DA, Zarif L. Pharmacokinetics and tissue distribution after intravenous administration of a single dose of amphotericin B cochleates, a new lipid-based delivery system. J Pharm Sci. 2002;91(8):1827–37. doi:10.1002/jps.10173.

    Article  CAS  PubMed  Google Scholar 

  52. Papahadjopoulos D, Vail WJ, Jacobson K, Poste G. Cochleate lipid cylinders: formation by fusion of unilamellar lipid vesicles. Biochim Biophys Acta. 1975;394(3):483–91.

    Article  CAS  PubMed  Google Scholar 

  53. Zarif L. Drug delivery by lipid cochleates. Methods Enzymol. 2005;391(18):314–29. doi:10.1016/S0076-6879(05)91018-5.

    Article  CAS  PubMed  Google Scholar 

  54. Zarif L, Graybill JR, Perlin D, Najvar L, Bocanegra R, Mannino RJ. Antifungal activity of amphotericin B cochleates against Candida albicans infection in a mouse model. Antimicrob Agents Chemother. 2000;44(6):1463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Syed UM, Woo AF, Plakogiannis F, Jin T, Zhu H. Cochleates bridged by drug molecules. Int J Pharm. 2008;363(1–2):118–25. doi:10.1016/j.ijpharm.2008.06.026.

    Article  CAS  PubMed  Google Scholar 

  56. Jin T, Zarif L, Mannino RJ. Nano-cochleate formulations, process of preparation and method of delivery of pharmaceutical agents., United States Patent and Trademark Office. 2000. http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/6153217. Accessed 25 Mar 2017.

  57. Wasankar SR, Makeshwar KV, Deshmukh AD, Burgate RM. Nanocochleate: a review. Res J Pharma Dosage Forms Tech. 2012;4:153–9.

    Google Scholar 

  58. Delmas G, Park S, Chen ZW, Tan F, Kashiwazaki R, Zarif L, et al. Efficacy of orally delivered cochleates containing amphotericin B in a murine model of aspergillosis. Antimicrob Agents Chemother. 2002;46(8):2704–7. doi:10.1128/AAC.46.8.2704-2707.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Serrano DR, Lalatsa A, Dea-Ayuela MA, Bilbao-Ramos PE, Garrett NL, Moger J, et al. Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles. Mol Pharm. 2015;12(2):420–31. doi:10.1021/mp500527x.

    Article  CAS  PubMed  Google Scholar 

  60. Matinas. Matinas BioPharma’s lead antifungal product candidate MAT2203 granted QIDP and Fast Rrack designations by the U.S FDA., Matinas BioPharma. 2016. http://www.matinasbiopharma.com/media/press-releases/detail/235/matinas-biopharmas-lead-antifungal-product-candidate. Accessed 25 March 2017.

  61. Manino R, Perlin D. Oral dosing of encochleated amphotericin B (CAmB): Rapid drug targeting to infected tissue in mice with invasive candidiasis. American Society of Microbiology's Interscience Conference on Antimicrobial Agents and Chemotherapy and International Society of Chemotherapy's International Congress of Chemotherapy and infection; San Diego, California. 2015.

  62. Biederdorf FA, Breithaupt I, Mannino R, Blum DE. Oral administration of amphotericin B (CAmB)) in humans: a phase I study of tolerability and pharmacokinetics., Matinas Biopharma. . 2016. http://content.equisolve.net/_b471c5f8d5c5228ccb2fffeb89c7d38b/matinasbiopharma/db/128/515/pdf/CAmB-Focus-Phase-1-Poster.pdf. Accessed 25 Mar 2017.

  63. Cabib E. Differential inhibition of chitin synthetases 1 and 2 from Saccharomyces cerevisiae by polyoxin D and nikkomycins. Antimicrob Agents Chemother. 1991;35(1):170–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hector RF, Zimmer BL, Pappagianis D. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. Antimicrob Agents Chemother. 1990;34(4):587–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Clemons KV, Stevens DA. Efficacy of nikkomycin Z against experimental pulmonary blastomycosis. Antimicrob Agents Chemother. 1997;41(9):2026–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Graybill JR, Najvar LK, Bocanegra R, Hector RF, Luther MF. Efficacy of nikkomycin Z in the treatment of murine histoplasmosis. Antimicrob Agents Chemother. 1998;42(9):2371–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Shubitz LF, Roy ME, Nix DE, Galgiani JN. Efficacy of nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs. Med Mycol. 2013;51(7):747–54. doi:10.3109/13693786.2013.770610.

    Article  CAS  PubMed  Google Scholar 

  68. Nix DE, Swezey RR, Hector R, Galgiani JN. Pharmacokinetics of nikkomycin Z after single rising oral doses. Antimicrob Agents Chemother. 2009;53(6):2517–21. doi:10.1128/AAC.01609-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shubitz LF, Trinh HT, Perrill RH, Thompson CM, Hanan NJ, Galgiani JN, et al. Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials. J Infect Dis. 2014;209(12):1949–54. doi:10.1093/infdis/jiu029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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. 2012;7(9):1520–8. doi:10.1021/cb300235m.

    Article  CAS  PubMed  Google Scholar 

  71. Watanabe NA, Miyazaki M, Horii T, Sagane K, Tsukahara K, Hata K. E1210, a new broad-spectrum antifungal, suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis. Antimicrob Agents Chemother. 2012;56(2):960–71. doi:10.1128/AAC.00731-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Miyazaki M, Horii T, Hata K, Watanabe NA, Nakamoto K, Tanaka K, et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob Agents Chemother. 2011;55(10):4652–8. doi:10.1128/AAC.00291-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hata K, Horii T, Miyazaki M, Watanabe NA, Okubo M, Sonoda J, 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. 2011;55(10):4543–51. doi:10.1128/AAC.00366-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Christopherson RI, Lyons SD, Wilson PK. Inhibitors of de novo nucleotide biosynthesis as drugs. Acc Chem Res. 2002;35(11):961–71. doi:10.1021/ar0000509.

    Article  CAS  PubMed  Google Scholar 

  75. Oliver JD, Sibley GE, Beckmann N, Dobb KS, Slater MJ, McEntee L, et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci USA. 2016;113(45):12809–14. doi:10.1073/pnas.1608304113.

    Article  CAS  PubMed Central  Google Scholar 

  76. Wiederhold NP, Law D, Birch M. Dihydroorotate dehydrogenase inhibitor F901318 has potent in vitro activity against Scedosporium species and Lomentospora prolificans. J Antimicrob Chemother. 2017. doi:10.1093/jac/dkx065.

    Google Scholar 

  77. Kennedy T, Allen G, Steiner J, Heep M, Birch M. Assessment of the duration of infusion on the tolerability and repeat dose pharmacokinetics of F901318 in healthy volunteers. ECCMID 2017; Vienna, Austria. 2017.

  78. Kennedy T, Allen G, Steiner J, Heep M, Oliver J, Sibley G, et al. Multiple dose pharmacokinetics of an immediate-release tablet formulation of F901318 in healthy male and female subjects. Vienna: ECCMID; 2017.

    Google Scholar 

  79. Casadevall A. Antibody immunity and invasive fungal infections. Infect Immun. 1995;63(11):4211–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Fleuridor R, Zhong Z, Pirofski L. A human IgM monoclonal antibody prolongs survival of mice with lethal cryptococcosis. J Infect Dis. 1998;178(4):1213–6.

    Article  CAS  PubMed  Google Scholar 

  81. Mukherjee J, Scharff MD, Casadevall A. Protective murine monoclonal antibodies to Cryptococcus neoformans. Infect Immun. 1992;60(11):4534–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Rodrigues ML, Shi L, Barreto-Bergter E, Nimrichter L, Farias SE, Rodrigues EG, et al. Monoclonal antibody to fungal glucosylceramide protects mice against lethal Cryptococcus neoformans infection. Clin Vaccine Immunol. 2007;14(10):1372–6. doi:10.1128/CVI.00202-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rosas AL, Nosanchuk JD, Casadevall A. Passive immunization with melanin-binding monoclonal antibodies prolongs survival of mice with lethal Cryptococcus neoformans infection. Infect Immun. 2001;69(5):3410–2. doi:10.1128/IAI.69.5.3410-3412.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71(9):5273–9. doi:10.1128/IAI.71.9.5273-5279.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nosanchuk JD, Steenbergen JN, Shi L, Deepe GS Jr, Casadevall A. Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum. J Clin Invest. 2003;112(8):1164–75. doi:10.1172/JCI19361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chaturvedi AK, Kavishwar A, Shiva Keshava GB, Shukla PK. Monoclonal immunoglobulin G1 directed against Aspergillus fumigatus cell wall glycoprotein protects against experimental murine aspergillosis. Clin Diagn Lab Immunol. 2005;12(9):1063–8. doi:10.1128/CDLI.12.9.1063-1068.2005.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Cenci E, Mencacci A, Spreca A, Montagnoli C, Bacci A, Perruccio K, et al. Protection of killer antiidiotypic antibodies against early invasive aspergillosis in a murine model of allogeneic T-cell-depleted bone marrow transplantation. Infect Immun. 2002;70(5):2375–82. doi:10.1128/IAI.70.5.2375-2382.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Buissa-Filho R, Puccia R, Marques AF, Pinto FA, Munoz JE, Nosanchuk JD, et al. The monoclonal antibody against the major diagnostic antigen of Paracoccidioides brasiliensis mediates immune protection in infected BALB/c mice challenged intratracheally with the fungus. Infect Immun. 2008;76(7):3321–8. doi:10.1128/IAI.00349-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gigliotti F, Haidaris CG, Wright TW, Harmsen AG. Passive intranasal monoclonal antibody prophylaxis against murine Pneumocystis carinii pneumonia. Infect Immun. 2002;70(3):1069–74. doi:10.1128/IAI.70.3.1069-1074.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nascimento RC, Espindola NM, Castro RA, Teixeira PA, Loureiro y Penha CV, Lopes-Bezerra LM, et al. Passive immunization with monoclonal antibody against a 70-kDa putative adhesin of Sporothrix schenckii induces protection in murine sporotrichosis. Eur J Immunol. 2008;38(11):3080–9. doi:10.1002/eji.200838513.

    Article  CAS  PubMed  Google Scholar 

  91. Bugli F, Cacaci M, Martini C, Torelli R, Posteraro B, Sanguinetti M, et al. Human monoclonal antibody-based therapy in the treatment of invasive candidiasis. Clin Dev Immunol. 2013;2013:403121. doi:10.1155/2013/403121.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Karwa R, Wargo KA. Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother. 2009;43(11):1818–23. doi:10.1345/aph.1M218.

    Article  CAS  PubMed  Google Scholar 

  93. Matthews RC, Rigg G, Hodgetts S, Carter T, Chapman C, Gregory C, et al. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother. 2003;47(7):2208–16. doi:10.1128/AAC.47.7.2208-2216.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hodgetts S, Nooney L, Al-Akeel R, Curry A, Awad S, Matthews R, et al. Efungumab and caspofungin: pre-clinical data supporting synergy. J Antimicrob Chemother. 2008;61(5):1132–9. doi:10.1093/jac/dkn075.

    Article  CAS  PubMed  Google Scholar 

  95. Pachl J, Svoboda P, Jacobs F, Vandewoude K, van der Hoven B, Spronk P, et al. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis. 2006;42(10):1404–13. doi:10.1086/503428.

    Article  CAS  PubMed  Google Scholar 

  96. Refusal CHMP assessment report for mycograb., European Medicines Agency. 2007. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000658/WC500070523.pdf. Accessed 25 March 2017.

  97. Larsen RA, Pappas PG, Perfect J, Aberg JA, Casadevall A, Cloud GA, 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. 2005;49(3):952–8. doi:10.1128/AAC.49.3.952-958.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci. 2013;368(1612):20120431. doi:10.1098/rstb.2012.0431.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Zip Code 14080, Mexico City, Mexico

    Maria F. Gonzalez-Lara

  2. Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Zip Code 14080, Mexico City, Mexico

    Jose Sifuentes-Osornio

  3. Division of Infectious Diseases, McGovern Medical School, Medical Director of Epidemiology, Memorial Hermann Texas Medical Center, 6431 Fanning MSB 2.112, Houston, TX, USA

    Luis Ostrosky-Zeichner

Authors
  1. Maria F. Gonzalez-Lara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose Sifuentes-Osornio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luis Ostrosky-Zeichner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria F. Gonzalez-Lara.

Ethics declarations

Conflicts of interest

Relevant to this manuscript, L.O. has received grants, consulting and /or speaking fees from the following companies: Merck, Astellas, Pfizer, Cidara, Scynexis, and Gilead. J.S.O has received research grants from Senosiain, Pfizer, Merck Sharp & Dohme, Sanofi Pasteur, AstraZeneca, and bioMérieux; personal fees from Pfizer, Merck Sharp& Dohme, and Sanofi Pasteur; and non-financial support from Pfizer, Merck Sharp & Dohme, Sanofi Pasteur, and bioMérieux. M.F.G.L declares no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gonzalez-Lara, M.F., Sifuentes-Osornio, J. & Ostrosky-Zeichner, L. Drugs in Clinical Development for Fungal Infections. Drugs 77, 1505–1518 (2017). https://doi.org/10.1007/s40265-017-0805-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-017-0805-2

Search

Navigation