Genetic analysis of Candida glabrata shows new genetic
sources of drug tolerance
20 August 2014
The Max F. Perutz Laboratories in Vienna has coordinated a
genetic study of Candida glabrata that has discovered 28 new genes that are partly responsible for the yeast's
tolerance of common drugs.
The working group led by Karl Kuchler at the Max F. Perutz
Laboratories (MFPL) — a research and training centre run jointly
between the University of Vienna and the Medical University of
Vienna at the Vienna Biocenter Campus — coordinated the international
study aimed at researching new tolerance and virulence genes in
Candida labrata. During this process, genetic
methods were used to generate one of the world's three largest
libraries of "knock-out fungi". More than 600 fungus mutations were
created from which a single gene was specifically removed.
Now published in the journal PLoS Pathogens, the molecular
analysis of the Candida glabrata fungus mutations revealed
28 new genes that confer anti-fungal tolerance, especially to the
popular drug Caspofungin. The study, in which the coordinators in
Vienna also collaborated with groups from the Johns Hopkins
University, the Institut Pasteur in Paris, the Fraunhofer Institute
in Stuttgart, Imperial College in London and the Genomics Institute
in Barcelona, also identified new intra-cellular stress sensors and
signal transmitters in Candida glabrata. Removing these
characteristics genetically leads to marked sensitivity to all of
the anti-fungal medications currently used in clinical practice —
"Since genetically removing these virulence factors from a
Candida glabrata patient isolates markedly reduces their
virulence as well as dramatically increases the fungal pathogens'
sensitivity to medications, these signal transmitters are the best
points of attack for the development of new and highly effective
anti-fungal therapies," says Karl Kuchler from the MFPL.
"These findings represent a new milestone in the discovery and
characterisation of Candida glabrata resistance genes,
laying the foundations for the development of new anti-fungal
medications. This means that, in future, it will be possible to
treat the often fatal invasive infections with pathogenic fungi in a
more targeted and efficient manner."
A few dozen types of harmful fungi claim more than 1.5 million
human lives every year. Especially people with a severely weakened
immune system are at particular risk of infections with yeasts of
the Candida species, with invasive infections being fatal in around 40% of
cases. Medications are expensive, and fungi are increasingly
Worldwide, more than €8 billion is spent worldwide on anti-fungal
medications, and the overall costs of treating the conditions caused
by pathogenic fungi exceed hundreds of billions worldwide. The
second-most common Candida fungus harmful to humans,
Candida glabrata,, is a major clinical problem since it has
sophisticated natural tolerance and can demonstrate resistance
triggered by anti-fungal therapy to the most important medications.
As a result, infections with Candida glabrata need to be
treated with very expensive drugs such as Caspofungin. Caspofungin
blocks the biogenesis of components of the carbohydrate-rich cell
wall, which is only found in fungi. The treatment of Candida
glabrata, however, is becoming increasingly difficult due to
the fact that anti-fungal resistance is common, the costs of
Caspofungin are very high and because the frequency of infections
with Candida glabrata has increased tremendously.
Schwarzmüller T et al. Systematic Phenotyping of a
Large-Scale Candida glabrata Deletion Collection Reveals Novel
Antifungal Tolerance Genes. PLoS Pathogens 10: e1004211.