Bioscience (master's two years)

Development of novel treatments for drug-resistant Candida infections

Fungal infections are a global increasing problem and development of antimycotic resistance it a major complication. This project aims to find and develop new antimycotics to treat drug-resistant infections.

Background

The increase of antimicrobial resistance to drugs is one of the biggest health threats that modern society is facing. A recent report estimates that if we do not revert the current trend, by 2050 untreatable infections will cause 10 million deaths a year, one every three seconds. Among the drug-resistant infections one particularly worrisome pathogen is Candida glabrata. Although it is naturally part of the human flora, in immunocompromised patients it can overcome the weaken immune system, causing bloodstream infections that without treatment will cause patient’s death. Unfortunately, Candida glabrata is naturally highly resistant to the first line of antifungal agents (Azoles) and it readily acquires resistance to the second line of antimycotics (Echinocandins). Indeed, the number of echinocandin resistant strains isolated in the clinic has doubled in the last 10 years.  If we do not find new antimycotics the majority of C. glabrata infections may become untreatable within the next decade, turning organ transplantations or anticancer treatments, including chemotherapy or bone marrow transplants, into very high-risk procedures.      

Goal

The goal of this project is to find new compounds to target drug-resistant C. glabrata infections and to understand the molecular mechanisms underlying antifungal resistances. To reach our goal we will face the problem using three complementary approaches:

1. Drug screening approach: We will screen a large library of uncharacterized compounds to find those that specifically kill drug-resistant fungi without affecting human cells. 

2. Genetic screening approach: Antifungal resistances are caused by genetic mutations. However as a side effect, these mutations alter the normal homeostasis of the cells. To cope with that, drug-resistant cells must activate molecular compensatory mechanisms that then become essential for these mutants. We will find and target these mechanisms.

3. Structural biology approach. We will co-crystallize the Fks1-echinocandin complex to investigate the structural consequences of drug-resistant mutations in Fks1. This knowledge will open up the possibility of performing in-silico drug screenings as well as chemical modifications on echinocandins to treat echinocandin-resistant infections.  

The ultimate goal of this research is to develop new therapies for patients suffering from drug-resistant fungal infections.

 

What we offer to the student

  • Experience in microbiology techniques and fungal genetics.
  • Experience in DNA manipulation, amplification and analysis.
  • Experience in protein purification and analysis.
  • Experience in state-of the-art microscopy, including high-content platforms.   
  • Training in software development for high-throughput analysis.
  • Training in transferrable skills: presentations, project writing or project planning.
  • The opportunity of joining a highly dynamic multidisciplinary team in an international environment.
  • The chance to research in one of the “hottest” biological topics of the next decade. 

 

Our research group

Our research group is led by Jorrit Enserink and consists of 12 members from 6 different countries. One of our research areas is fungal resistance to drugs and the development of new therapies to treat drug-resistant infections. The group has long experience in supervision of master- and PhD students.

We are part of the Department for Molecular Cell Biology at Radiumhospitalet, where we share facilities, reagents and expertise with other research groups.

Veiledere:

Ignacio Garcia

Jorrit Enserink

 

Published Mar. 22, 2018 10:28 AM - Last modified Apr. 19, 2018 8:13 AM

Supervisor(s)

Scope (credits)

60