Drug repurposing according to mechanism of action of an antifungal protein to inhibit Candida biofilms
(OTKA K 146131)
Principal Investigator: László Galgóczy
Duration: 48 moths (2024-2027)
As a consequence of the increasing number of fungal infections caused by antifungal drug-resistant Candida
biofilms, there is an urgent need to develop new and effective biofilm inhibitory strategies against the most
prevalent clinically important species, such as Candida albicans and Candida auris.
The Neosartorya fischeri
antifungal protein 2 (NFAP2) is considered as a potential candidate for this purpose as it shows inhibitory and
eradication activities on Candida biofilms. However, development of an NFAP2-based anti-biofilm drug is cost-
and time-consuming.
Drug repurposing represents a time- and cost-effective straightforward strategy for
identification of new applicability of existing drugs beyond the original medical indication. The present
project focuses on these aspects, and aims to (1) investigate the biofilm inhibitory mechanism of NFAP2 in C.
albicans and C. auris, (2) identify the direct and indirect molecular components of the Candida biofilm
inhibitory activity of NFAP2 to find protein targets for a drug repurposing strategy, (3) identify NFAP2 binding
pockets of the directly targeted proteins, and search for molecules with binding affinity to these pockets from
approved drug, experimental drug and traditional Chinese medicine libraries, (4) investigate the potential,
safe, and future-proof applicability of the most promising candidate molecule. These goals will be achieved by
senior and young scientists, and supervised university students applying a multidisciplinary approach.
As a final outcome of the project, we will be able to make suggestions for a new and effective Candida biofilm
eradication strategy for the medicine.
Supported by Hungarian National Research, Development
and Innovation Office.
Antifungal proteins - Investigation of antifungal mechanism and biological
role for new therapeutic approaches (OTKA FK 134343)
Principal Investigator: László Galgóczy
Duration: 48 moths (2020-2024)
In the consequence of the emerging number of drug-resistant fungal strains the
incidences of fungal infections dramatically increased worldwide. The
facts that only a few classes of antifungal drugs are available and that
they can cause serious side-effects and damage the host’s organs
permanently hamper patient management. Therefore, there is a substantial
demand for development of fundamental new, effective and safely applicable
antifungal strategies to prevent and treat fungal infections.
The features of the small molecular weight, cysteine-rich, cationic antifungal proteins
secreted by the filamentous ascomycete, Neosartorya (Aspergillus) fischeri
(crAFPs) correspond well to these challenges.
One of the key steps in their application as antifungals drugs is an understanding the molecular
mechanisms behind the antifungal activity.
The present project focuses to
this aspect, (1) investigation of their antifungal mechanism in human
pathogenic fungi and biological role in the native producer, and (2)
identification the molecular components of these mechanisms. Furthermore,
to (3) identify or design potential drug candidate compounds acting on
these molecular components, and (4) prove their safe applicability in the
clinical therapy.
These goals will be achieved by young and senior
scientists, and supervised university students applying a
multidisciplinary approach that integrates transcriptome meta-analysis,
virtual ligand screenings and docking techniques, antifungal and toxicity
tests.
As a final outcome of the accomplished project, we will be able to
make suggestions for a new and effective crAFP target-based antifungal
strategy.
Supported by Hungarian National Research, Development and
Innovation Office.