Neurokinin-1 receptor antagonists as antifungal enhancers (SJ-21-0021)

St. Jude Reference #SJ-21-0021

Description

Researchers at St. Jude have found that combining sterol biosynthesis inhibitors, most notably the triazole antifungals (the largest and most utilized class of antifungal agents), with the NK1-anatgonist class of antiemetic agents (currently marketed only for anti-nausea effects), significantly enhances the antifungal effect of the antifungal agents. This effect is even present across a panel of highly antifungal-resistant clinical isolates of Candida auris (an FDA threat level urgent antimicrobial resistant pathogen of great clinical concern), as well as the most common pathogenic mold, Aspergillus fumigatus. This combination also enhances the ability of triazole antifungals to kill fungus rather than just inhibit its growth. I have also found that select NK1-antagonists, such as netupitant and rolapitant, independently exert a fungicidal antifungal effect at higher concentrations.                                                                             

This development could be used to enhance the treatment of patients with difficult to treat fungal infections such as those caused by Candida spp., Aspergillus spp., Cryptococcus spp., Mucor spp., Rhizopus spp., etc. These agents could potentially be co-formulated in intravenous, oral, or topical application. Additionally, these agents could be combined through the application of a liposome, nano particle, or molecular scaffold delivery system. Furthermore, the combination of these agents could be used as a disinfectant to remove difficult to kill fungal organisms from surfaces in laboratory or medical settings and could represent a uniquely potent combination for the treatment of serious infections using oral formulations.

Commercially available agents of the individual drug classes include:

• Triazoles (fluconazole, voriconazole, isavuconazole (as the prodrug isavuconazonium sulfate), itraconazole, posaconazole)
• Additional sterol biosynthesis inhibitors (terbinafine, fenpropimorph)
• NK1-antagonists (aprepitant, fosaprepitant (the prodrug formulation of aprepitant), rolapitant, netupitant (in a coformulation with palonsetron), maropitant (veterinary use only in the US), casopitant (investigational), vaptreotide, CP-122721 (investigational)

Keywords

Ssterol biosynthesis inhibitors, triazole antifungals, NK1-anatgonist, antiemetic agents, antifungal, Aspergillus, Cryptococcus, Mucor, Rhizopus, nano particle, molecular scaffold delivery system, disinfectant, Triazoles, fluconazole, voriconazole, isavuconazole, isavuconazonium sulfate, itraconazole, posaconazole, sterol biosynthesis inhibitor, terbinafine, fenpropimorph, aprepitant, fosaprepitant, aprepitant, rolapitant, netupitant, palonsetron, maropitant, casopitant, vaptreotide, CP-122721.

Granted patents or published applications

International patent application WO 2023/220224 published May 2023

Related scientific references

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