Volume : 11, Issue : 02, February – 2024
Title:
UNVEILING TOMORROW’S ANTIFUNGALS: A COMPREHENSIVE REVIEW OF RECENT PIPELINE ADVANCEMENTS
Authors :
J.S Venkatesh, Upendra N, Mohankumar L, Mohsin Ahmed, Aswin Santosh Nair, Suraj Prabhakar Shetty
Abstract :
The treatment of invasive fungal infections is limited to a range of drugs from five recognized classes of antifungal therapy and is linked to considerable morbidity and death. In reality, dose-limiting toxicities, medication interactions, and delivery methods frequently place restrictions on the use of currently available antifungal medications. The need for the discovery of new antifungals, especially those with unique modes of action, has arisen from the increased incidence of invasive fungal infections, rising resistance rates, and the practical limits of current treatments. An overview of antifungal drugs at different phases of clinical development is provided in this article. We’ll talk about the latest additions to the current family of antifungal medications, which includes the highly bioavailable azole SUBA-itraconazole, the oral amphotericin B cochleate, and the long-acting echinocandin rezafungin, which can be used once a week. We will also evaluate new first-in-class drugs including olorofim, an oral pyrimidine synthesis inhibitor with a broad range of action and an oral formulation, and ibrexafungerp, an oral glucan synthase inhibitor with effectiveness against a variety of resistant fungal isolates. We will also look at several other novel antifungal drugs and classes, such as MGCD290, tetrazoles, and fosmanogepix.
Cite This Article:
Please cite this article in press J.S.Venkatesh et al., Unveiling Tomorrow’s Antifungals: A Comprehensive Review Of Recent Pipeline Advancements , Indo Am. J. P. Sci, 2024; 11 (02).
Number of Downloads : 10
References:
1. McCarthy, M.W.; Kontoyiannis, D.P.; Cornely, O.A.; Perfect, J.R.; Walsh, T.J. Novel agents and drug targets to meet the challenges of resistant fungi. J. Infect. Dis. 2017, 216, S474–S483.
2. Van Daele, R.; Spriet, I.; Wauters, J.; Maertens, J.; Mercier, T.; van Hecke, S.; Brüggemann, R. Antifungal drugs: What brings the future? Med. Mycol. 2019, 57, S328–S343.
3. Perfect, J.R. The antifungal pipeline: A reality check. Nat. Rev. Drug Discov. 2017, 16, 603–616.
4. Nguyen, M.-V.H.; Davis, M.R.; Wittenberg, R.; Mchardy, I.; Baddley, J.W.; Young, Y.; Odermatt, A.; Thompson, G.R., III. Posaconazole Serum Drug Levels Associated with Pseudohyperaldosteronism. Clin. Infect. Dis. 2019.
5. Thompson, G.R.; Chang, D.; Wittenberg, R.R.; McHardy, I.; Semrad, A. In vivo 11_-hydroxysteroid dehydrogenase inhibition in posaconazole-induced hypertension and hypokalemia. Antimicrob. Agents Chemother. 2017, 61.
6. Thompson, G.R.; Krois, C.R.; A_olter, V.K.; Everett, A.D.; Varjonen, E.K.; Sharon, V.R.; Singapuri, A.; Dennis, M.; McHardy, I.; Yoo, H.S.; et al. Examination of fluconazole-induced alopecia in an animal model and human cohort. Antimicrob. Agents Chemother. 2019, 63.
7. Qu, Y.; Fang, M.; Gao, B.X. Itraconazole decreases left ventricular contractility in isolated rabbit heart: Mechanism of action. Toxicol. Appl. Pharmacol. 2013, 268, 113–122.
8. Thompson, G.R.; Cadena, J.; Patterson, T.F. Overview of Antifungal Agents. Clin. Chest. Med. 2009, 30, 203–215.
9. Balfour, J.A.; Faulds, D. Drug Evaluation Terbinafine a Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Superficial Mycoses. Drugs 1992, 43, 259–284.
10. Nield, B.; Larsen, S.R.; van Hal, S.J. Clinical experience with new formulation SUBA®-itraconazole for prophylaxis in patients undergoing stem cell transplantation or treatment for hematological malignancies. J. Antimicrob. Chemother. 2019, 74, 3049–3055.
11. Abuhelwa, A.Y.; Foster, D.J.R.; Mudge, S.; Hayes, D.; Upton, R.N. Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob. Agents Chemother. 2015, 59, 5681–5696.
12. Lindsay, J.; Mudge, S.; Thompson, G.R. E_ects of food and omeprazole on a novel formulation of super bioavailability itraconazole in healthy subjects. Antimicrob. Agents Chemother. 2018, 62.
13. Lindsay, J.; Sandaradura, I.;Wong, K.; Arthur, C.; Stevenson,W.; Kerridge, I.; Fay, K.; Coyle, L.; Greenwood, M. Serum levels, safety and tolerability of new formulation SUBA-itraconazole prophylaxis in patients with hematological malignancy or undergoing allogeneic stem cell transplantation. J. Antimicrob. Chemother. 2017, 72, 3414–3419.
14. Sandison, T.; Ong, V.; Lee, J.; Thye, D. Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults. Antimicrob. Agents Chemother. 2017, 61.
15. Gangneux, J.-P.; Lortholary, O.; Cornely, O.; Pagano, L. 9th Trends in Medical Mycology Held on 11–14 October 2019, Nice, France, Organized under the Auspices of EORTC-IDG and ECMM. J. Fungi 2019, 5, 95.
16. Zhao, Y.; Prideaux, B.; Nagasaki, Y. Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model. Antimicrob. Agents Chemother. 2017.
17. Lepak, A.J.; Zhao, M.; Andesa, D.R. Pharmacodynamic evaluation of rezafungin (CD101) against Candida auris in the neutropenic mouse invasive candidiasis model. Antimicrob. Agents Chemother. 2018, 62.
18. Davis, M.R.; Donnelley, M.A.; Thompson, G.R. Ibrexafungerp: A novel oral glucan synthase inhibitor. Med. Mycol. 2019.
19. Aruanno, M.; Glampedakis, E.; Lamoth, F. Echinocandins for the Treatment of Invasive Aspergillosis: From Laboratory to Bedside. Antimicrob. Agents Chemother. 2019, 63.
20. Spec, A.; Pullman, J.; Thompson, G.R. MSG-10: A Phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis. J. Antimicrob. Chemother. 2019, 74, 3056–3062.
21. Nunnally, N.S.; Etienne, K.A.; Angulo, D.; Lockhart, S.R.; Berkow, E.L. In Vitro Activity of Ibrexafungerp, a Novel Glucan Synthase Inhibitor against Candida glabrata Isolates with FKS Mutations. Antimicrob. Agents Chemother. 2019, 63.
22. Hope,W.; Mcentee, L.; Johnson, A.; Farrington, N.; Whalley, S.; Santoyo-Castelazo, A.; Birch, M.; Law, D.; Kennedy, T.; Heep, M.; et al. Session: OS173 Challenges in Antifungal Treatment against Aspergillus Fumigatus in a Rabbit Model of Invasive Pulmonary Aspergillosis (IPA); ECCMID: Viena, Austria, 2017.
23. 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: Viena, Austria, 2017.
24. Rivero-Menendez, O.; Cuenca-Estrella, M.; Alastruey-Izquierdo, A. In vitro activity of olorofim (F901318) against clinical isolates of cryptic species of Aspergillus by EUCAST and CLSI methodologies. J. Antimicrob. Chemother. 2019, 74, 1586–1590.
25. Wiederhold, N.P.; Najvar, L.K.; Jaramillo, R.; Olivo, M.; Birch, M.; Law, D.; Rex, J.H.; Catano, G.; Patterson, T.F. The orotomide olorofim is efficacious in an experimental model of central nervous system coccidioidomycosis. Antimicrob. Agents Chemother. 2018, 62.
26. Pfaller, M.A.; Messer, S.A.; Georgopapadakou, N.; Martell, L.A.; Besterman, J.M.; Diekema, D.J. Activity of MGCD290, a Hos2 histone deacetylase inhibitor, in combination with azole antifungals against opportunistic fungal pathogens. J. Clin. Microbiol. 2009, 47, 3797–3804.
27. Pfaller, M.A.; Rhomberg, P.R.; Messer, S.A.; Castanheira, M. In vitro activity of a Hos2 deacetylase inhibitor, MGCD290, in combination with echinocandins against echinocandin-resistant Candida species. Diagn. Microbiol. Infect. Dis. 2015.
28. Augenbraun, M.; Livingston, J.; Parker, R.; Lederman, R. Fluconazole and MGCD290 in Vulvo Vaginal Candidiasis (VVC): Results from a Randomized Phase II Study; IDWeek: San Francisco, CA, USA, 2013.
29. Gallis, H.A.; Drew, R.H.; Pickard,W.W. (Eds.) Amphotericin B: 30 Years of Clinical Experience. Rev. Infect. Disesases 1990, 12, 308–329.
30. Hamill, R.J. Amphotericin B formulations: A comparative review of efficacy and toxicity. Drugs 2013, 73, 919–934.
31. Santangelo, R.; Paderu, P.; Delmas, G.; Chen, Z.-W.; Mannino, R.; Zarif, L.; Perlin, D.S. Efficacy of oral cochleate-amphotericin B in a mouse model of systemic candidiasis. Antimicrob. Agents Chemother. 2000, 44, 2356–2360.
32. Shende, P.; Khair, R.; Gaud, R.S. Nanostructured cochleate: A multi-layered platform for cellular transportation of therapeutics. Drug Dev. Ind. Pharm. 2019, 45, 869–881.
33. Wiederhold, N.P.; Xu, X.;Wang, A.; Najvar, L.K.; Garvey, E.P.; Ottinger, E.A.; Alimardanov, A.; Cradock, J.; Behnke, M.; Hoekstra,W.J.; et al. In vivo efficacy of VT-1129 against experimental cryptococcal meningitis with the use of a loading dose-maintenance dose administration strategy. Antimicrob. Agents Chemother. 2018, 62, 1–10.
34. Hoekstra,W.J.; Garvey, E.P.; Moore,W.R.; Ra_erty, S.W.; Yates, C.M.; Schotzinger, R.J. Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 3455–3458.
35. Wiederhold, N.P.; Shubitz, L.F.; Najvar, L.K.; Jaramillo, R.; Olivo, M.; Catano, G.; Trinh, H.T.; Yates, C.M.; Schotzinger, R.J.; Garvey, E.P.; et al. The novel fungal Cyp51 inhibitor VT-1598 is efficacious in experimental models of central nervous system coccidioidomycosis caused by Coccidioides posadasii and Coccidioides immitis. Antimicrob. Agents Chemother. 2018, 62, 1–7.
36. Nishimoto, A.T.; Wiederhold, N.P.; Flowers, S.A.; Zhang, Q.; Kelly, S.L.; Morschhäuser, J.; Yates, C.M.; Hoekstra,W.J.; Schotzinger, R.J.; Garvey, E.P.; et al. In vitro, activities of the novel investigational tetrazoles vt-1161 and vt-1598 compared to the triazole antifungals against azole-resistant strains and clinical isolates of Candida albicans. Antimicrob. Agents Chemother. 2019, 63, 1–11.
37. Hata, K.; Horii, T.; Miyazaki, M.; Watanabe, N.; Okubo, M.; Sonoda, J.; Nakamoto, K.; Tanaka, K.; Shirotori, S.; Murai, N.; et al. E_cacy 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, 4543–4551.
38. Alkhazraji, S.; Gebremariam, T.; Alqarihi, A. Fosmanogepix (APX001) is E_ective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis. Antimicrob. Agents Chemother. 2019.
39. Viriyakosol, S.; Kapoor, M.; Okamoto, S. APX001 and Other Gwt1 Inhibitor Prodrugs Are E_ective in Experimental Coccidioides immitis Pneumonia. Antimicrob. Agents Chemother. 2019, 63.
40. Kovanda, L.L.; Sullivan, S.M.; Smith, L.R.; Desai, A.V.; Bonate, P.L.; Hope, W.W. Population pharmacokinetic modeling of VL-2397, a novel systemic antifungal agent: Analysis of a single- And multiple-ascending-dose study in healthy subjects. Antimicrob. Agents Chemother. 2019, 63.
41. Abe, M.; Nakamura, S.; Kinjo, Y. E_cacy of T-2307, a novel arylamidine, against ocular complications of disseminated candidiasis in mice. J. Antimicrob. Chemother. 2019, 74, 1327–1332.
42. Shubitz, L.F.; Trinh, H.T.; Perrill, R.H. Modeling Nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials. J. Infect. Dis. 2014, 209, 1949–1954.
43. Rhein, J.; Huppler Hullsiek, K.; Tugume, L.; Nuwagira, E.; Mpoza, E.; Evans, E.E.; Kiggundu, R.; Pastick, K.A.; Ssebambulidde, K.; Akampurira, A.; et al. Adjunctive sertraline for HIV-associated cryptococcal meningitis: A randomised, placebo-controlled, double-blind phase 3 trial. Lancet Infect. Dis. 2019, 8, 843–851.
44. Wiederhold, N.P.; Patterson, T.F.; Srinivasan, A. Repurposing auranofin as an antifungal: In vitro activity against a variety of medically important fungi. Virulence 2017, 8, 138–142.
45. Dolan, K.; Montgomery, S.; Buchheit, B.; DiDone, L.; Wellington, M.; Krysan, D.J. Antifungal activity of tamoxifen: In vitro and in vivo activities and mechanistic characterization. Antimicrob. Agents Chemother. 2009, 53, 3337–3346.
46. Villanueva-Lozano, H.; Treviño-Rangel, R.J.; Téllez-Marroquín, R.; Bonifaz, A.; Rojas, O.C. In vitro inhibitory activity of sertraline against clinical isolates of Sporothrix schenckii. Rev. Iberoam Micol. 2019, 36, 139–141.