Overcoming fungal resistance

There are only four classes of drugs in the market to treat systemic fungal infection, with the azole class serving a front line role. European researchers have found drug-resistant strains of fungal species such as Aspergillus and Candida in about 20 to 30 % of patients. This is a serious issue as no effective treatment alternatives are available to clinicians.

Leading European small and medium-sized enterprises (SMEs) and academics have joined forces on the NOFUN (Novel antifungals to treat resistant organisms) project to develop novel classes of antifungals and to identify drug targets. This consortium had previously identified antifungal molecules that are potent against multidrug-resistant fungal pathogens, including Aspergillus, Candida, Scedopsporium, Fusarium and Zygomyces species. During the course of this project they plan to validate the antifungal efficacy as well as safety of these compounds. Another aspect of their research involves determining the drug mechanism of action to produce optimised lead compound series for preclinical studies.

During the first project phase itself, NOFUN made significant progress. To begin with, they worked on improving synthetic routes and are determining the structure-activity relationship around the antifungal molecule. Through key substitutions, researchers shortlisted two variants of the key pharmacophore and made multiple analogues.

The 'Type two' analogues showed significantly improved in vitro antifungal activity even against the Candida species, unlike the 'Type one' analogue. These analogues were further tested to assess their bioavailability as well as clearance, returning highly encouraging results for oral administration. The two most promising compounds among these are now being re-synthesised at gram scale for further testing.

NOFUN made significant inroads with regard to elucidating the mechanism of action of the newly identified antifungal compound. As a result, they identified a previously unknown druggable target that could prove effective against Aspergillus fumigatus. They are currently evaluating the viability of this drug target.

Successful realisation of a potent antifungal drug candidate for oral administration would mean that clinicians have a practical recourse to treat drug-resistant infections. Commercialisation of such a drug would not only be life-saving, it would also enhance the competitiveness of the participating SMEs via a patent.