New therapeutic compounds against resistand fungi

A silent microbial pandemic, comparable to antibiotic resistance in bacteria, is related to fungi. More than 150 million people acquire serious fungal diseases per year. Among these, invasive fungal infections (IFIs) are killing more than 1.5 million people globally. Currently, global reports reveal that rapidly spreading drug-resistant strains of Candida species and other fungi including Aspergillus, in lung infections and systemic infections, have become resistant against the commonly used azole drugs on the market. Our research group SYNFAS at the Pharmaceutical Department, University of Oslo (UiO), develops antimicrobial products. The project has its outspring in SYNFAS, whose project leader has 40-year experience with drug discovery and strategic IP work. SYNFAS has invented several technologies effective against clinical drug-resistant bacteria, among them, the ZinChel technology has resulted in several patents, research grants and a bio-startup (Adjutec Pharma AS). During development of a library of antibacterial agents, SYNFAS and colleagues in the Genome Dynamics (GD) group at Oslo University Hospital/UiO discovered an important spinoff: the synthetic intermediate TPA-CO2Me had activity against multidrug-resistant tuberculosis (MDR-TB). Here in the FUNGOmere qualification project, we demonstrate the startling discovery that the chemical class to which TPA-CO2Me belong, also has effect against drug-resistant fungi. We have shown that TPA-CO2Me-derivatives are active against a range of yeast species, including the multidrug-resistant Candida auris. The synthesis and testing of TPA-CO2Me-based drug candidates was performed at UiO and OUS. In FUNGOmere, we have: a) completed component synthesis, b) conducted a proof of concept (PoC) microbiological study at OUS to test and verify the antifungal effect, and c) secured new IP, representing a huge medical need and substantial market potential. Synthesis of 10 drug candidates was performed at UiO. The new TPA-CO2Me derivatives were tested in a proof of concept (PoC) microbiological study at OUS against 7 different fungal species that cause disease in humans, including strains that are resistent against many of the commonly used antifungal drugs. Several of the new drug candidates exhibited significant antifungal effect in lab-testing in vitro against the fungal strains, and we are in the process of securing IP rights for these. The next step will be extended microbiological studies to verify and strengthen the antifungal effects of the best drug candidates and to develop chemistry manufacturing and control. The FUNGOmere project group is a team of experienced UiO/OUS employees with decades of experience and know-how from academia and pharmaceutical industry. Given the promising discoveries and results demonstrated in the FUNGOmere qualification project, the resulting product would have a large market potential and impact on society.

Antimikrobiell resistens er en stor trussel mot folkehelsen. Internasjonale rapporter viser nå at raskt spredende sopp-arter, inkludert Candida, i lungeinfeksjon og i systemiske infeksjoner, har blitt resistente mot azol-medisinene på markedet. Disse 5-6 "siste utvei" azolproduktene kan se tilbake på 20-50 års tilstedeværelse på markedet, men de er nå ineffektive, og ny innovasjon og alternativ medisin er presserende. FUNGOmere-prosjektet har lykkes med å designe og teste legemiddelkandidater til bruk mot sopp gjennom et tverrfaglig samarbeid mellom kjemikere, leger og mikrobiologer. De nye kandidatene er effektive mot en rekke Candida-arter, inkludert den resistente Candida auris. Arbeidet har gitt erfaring og læring for alle parter, både i syntese, samarbeid og uttesting av legemiddelkandidater med hensyn på soppdrepende aktivitet. En masterstudent og en bachelorstudent hadde syntese av legemiddelkandidatene som deler av sine master- og bacheloroppgaver. Legemiddelkandidater med lovende effekt er oppdaget og videreutviklet, som kan danne grunnlaget for viktige soppmidler som pasienter kan få nytte av. Gitt de lovende funnene og resultatene demonstrert i FUNGOmere kvalifiseringsprosjektet utført ved UiO og OUS, vil prosjektet ha et stort markedspotensial og innvirkning på samfunnet. Interessentene i farmasøytisk virksomhet inkluderer pasienter, leger, medisinske representanter, forhandlere, grossister, sykehuspersonell og andre. Suksessen til FUNGOmere vil også ha positive sikkerhetseffekter for andre akademiske forskningsgrupper og deres studenter, FoU-leverandører, helsespesialister og pasienter i Norge og internasjonalt.