The appearance of resistance to antifungals is a very significant health problem, which accentuates the importance of developing new drugs and adapting existing ones. This is particularly important when considering life-threatening fungal infections treated in intensive care units.
Over time, several pathogens have developed resistance to traditional antifungals, such as some species of Candida non-albicans, e.g. C. glabatra e C. krusei. But also some recently discovered pathogens, such as Tintelnotia destructans e C. auris, were found to be resistant to currently used antifungals.
Several new antifungals are under development or approval. Although primarily developed for systemic administration, with the support of the pharmacist, the intravenous formulation can also be used as eye drops. In particular, if conventional therapy for ocular fungal infections fails, one of these new substances may prove to be suitable for treating mycoses, even at the ophthalmic level (e.g. in the treatment of fungal endophthalmitis).
New antifungal drug candidates for use in ophthalmology
- Fosmanopegix
It is a pro-drug that inhibits the Gwt1 protein, which is only found in the fungal cell wall. Specifically, its action prevents the formation of the cell wall from mannoproteins, causing the death of the fungal cell. Fosmanopegix showed a broad spectrum of activity in vitrowith proven effectiveness on Aspergillus, C. neoformans, Fusarium spp, Scedosporium spp. and Candida spp. included C. auris (except C. krusei). For the time being, Fosmanogepix can be used orally and intravenously. The substance is currently in phase II clinical trials and shows good tolerability.
- Ibrexafungerp
It is an inhibitor of β-1,3-glucan synthase of the fungal cell wall. Ibrexafungerp has proven effective against Candida spp. (also C. glabrata e C. krusei), Aspergillus spp. and Paecilomyces variotii. Ibrexafungerp also has potent antibiofilm activity. Ibrexafungerp is currently in phase III clinical trials and can be administered orally and intravenously.
- Olorofim
This substance belongs to the new class of antifungal orotomides, which inhibit the key enzyme dihydroorotate dehydrogenase (DHODH), which is required for pyrimidine biosynthesis. This inhibition leads to the disruption of phospholipid and protein synthesis in the cell wall. Olorofim can be administered orally or intravenously. It is mainly active against Aspergillus spp. and Scedosporium spp.
- Arilamidine
This antifungal is selectively transported into the fungal cell by a polyamine and inhibits mitochondrial function, thus having a fungicidal effect. Arylamidine works very well against Candida spp, Aspergillus spp. and Cryptococcus neoformans. Arylamidine is currently formulated as a solution for injection.
News on known substances
- Rezafungin
It is a new molecule of the echinocandin class. The spectrum of activity covers Candida spp., including C. auris, e Aspergillus spp.
- AR12
This substance is a celecoxib derivative, a Cox2 (cyclooxygenase 2) inhibitor, and was developed primarily as an anti-cancer agent. However, it has also shown good antifungal effects against Fusarium spp, Scedosporium apiospermum e Purpureocillium. The substance appears to act through two mechanisms: blocking acetyl-CoA synthetase 1 in fungal metabolism and reducing the host immune response.
- Amphotericin B encocleata
Amphotericin B is the oldest antifungal and has the advantage of being fungicidal, but is relatively toxic when used intravenously, while it is rather expensive in lipid formulations. The newly developed encocleated amphotericin B is much better tolerated and can be administered orally.
Bibliography
Dr. Carmelo Chines
Direttore responsabile