Drug repurposing according to mechanism of action of an antifungal protein to inhibit Candida biofilms
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 announced PhD 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 with a multidisciplinary approach that integrates protein localization
investigation, transcriptome analysis, whole genome sequencing, in vitro protein-protein interaction analysis,
in silico protein-protein docking, structure-based virtual screening, antifungal susceptibility testing,
laboratory microevolution, acute toxicity testing. 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.
Required skills:
Good communication in English. Basic knowledge in microbiology, protein works and bioinformatics.
The possibility of resistance development to antifungal proteins in fungi
In spite of the emerging number of life-threatening fungal infections
with high mortality rate caused by drug-resistant strains, and the
fact that the recently applied prolonged antifungal therapies can
seriously damage the host’s organs, the initiation to develop
effective and safely applicable new antifungal drugs is still
neglected for human welfare.
The already intensively studied antifungal proteins from filamentous Ascomycetes and their functional peptide
derivatives show high fungal-specificity and antimicrobial efficacy, thus they represent promising candidates to
develop fundamental new antifungal therapeutic strategies to overcome global antifungal challenges. Although,
knowledge about the potential of fungi to develop resistance mechanism to antifungal proteins, and about the
influence of antifungal protein resistance mechanisms on the physiology of fungi is still limited which hampers
their application as potential new antifungal drugs.
The announced PhD project focuses to these aspects. These goals will be achieved with a multidisciplinary
approach that integrates laboratory microevolution, metabolic fitness investigation, abiotic and biotic stress
factor tolerance analyses, genome sequencing, transcriptome meta-analysis, virulence analysis, antifungal
susceptibility testing, recombinant protein expression, and peptide synthesis.
The accomplishment of present project provides the first step toward
new fungal-specific drug development not just in the medical
treatment, but also in the pest control and food preservation with
worldwide economic and societal impact.
Required skills:
Basic knowledge in microbiological and protein works. Basic
bioinformatics knowledge.
Potential of novel defensin-like proteins from Solanum lycopersicum L.
in sustainable agriculture
As a consequence of the worldwide increase of enormous crop losses by
pre- and postharvest pesticide resistant phytopathogenic fungi, there
is a substantial demand to develop new antifungal strategies in
agriculture and food industry to support the increasing global food
consumption in the next decades.
Antifungal plant defensins are already considered as potential
biofungicides; however, several factors still limit their direct
agricultural application. These limitations are the high costs of
production, narrow antifungal spectrum, and potential toxic effects on
plant and humans/animals.
The announced PhD research project aims at proving the safe and
effective applicability of novel defensin-like proteins from tomato
plant (Solanum lycopersicum L.) and their rational designed peptide
derivatives as biofungicides in plant protection by investigating
their antifungal efficacy against phytopathogenic fungi and the
toxicity on different human cell lines and plant seedling;
furthermore, their application as protective or therapeutic agents
against fungal infections on plant leaves and roots.
The cost-effective production of tomato plant defensins applying a
fungal expression system is also in the focus of the project. In
addition, present project aimed to reveal the antifungal mechanisms of
these defensins in sensitive fungi, and their potential biostimulator
role in the plants to trigger the self-defence mechanisms or modulate
the plant development as responses to fungal infection.
The accomplishment of present project provides the first step toward
new fungal-specific biofungicide development in the pest control and
food preservation with worldwide economic and societal impact.
Required skills:
Basic knowledge in microbiological and protein works. Basic
bioinformatics knowledge.