Researchers identify how deadly fungus develops drug resistance - study

Researchers found the method by which the fungus C. neoformans develops resistance to antifungal drugs.

Cryptococcosis of lung in patient with AIDS. (photo credit: CDC/DR. EDWIN P. EWING, JR./PUBLIC DOMAIN/VIA WIKIMEDIA COMMONS)
Cryptococcosis of lung in patient with AIDS.
(photo credit: CDC/DR. EDWIN P. EWING, JR./PUBLIC DOMAIN/VIA WIKIMEDIA COMMONS)

Infections with the fungus Cryptococcus neoformans cause about 15% of death from acquired immunodeficiency syndrome (AIDS) due to drug resistance and a limited amount of available antifungal therapies. The cause of this drug resistance is not fully understood.

However, researchers have discovered how C. neoformans develops resistance to antifungal drugs in a new peer-reviewed study published in the scientific journal Nature Microbiology on Tuesday.

The researchers conducted a fluctuation analysis on the fungus to detect increased mutation rates and identified two hypermutator clinical isolates that had increased mutation rates when exposed to the substances rapamycin and FK506.

“The results are highly relevant for combating fungal infections in clinical practice, veterinary medicine and agriculture,” says Prof. Ulrich Kück, Senior Professor of General and Molecular Botany at Germany's Ruhr-Universität Bochum (RUB).

Fungal infections are on the rise in the Western hemisphere due to increasing life expectancy and the widespread use of immunosuppresants after organ transplants, he said.

Cryptococcus neoformans (credit: CDC/DR. LEANOR HALEY/PUBLIC DOMAIN/VIA WIKIMEDIA COMMONS)Cryptococcus neoformans (credit: CDC/DR. LEANOR HALEY/PUBLIC DOMAIN/VIA WIKIMEDIA COMMONS)

Cryptococcosis

“C. neoformans causes cryptococcosis, triggering acute infections in people who have a compromised immune system, with a mortality rate as high as 70%.”

Ruhr-Universität Bochum

Furthermore, C. neoformans causes cryptococcosis, triggering acute infections in people who have a compromised immune system, with a mortality rate as high as 70%, according to RUB. This is because drug-resistant fungi often evolve in hospitals, making it more difficult to treat patients, the university said.

However, segments of DNA called transposons may also be responsible for drug resistance in fungi. Transposons change their position, or “jump” in the genome, changing the functions of genes. If a transposon jumps into a gene related to drug susceptibility, it may become drug-resistant.

In the study, the researchers found mutations in resistant isolates that caused the small interfering RNA (siRNA) control, responsible for the mobility of transposons, to switch off, RUB said.

By adding a copy of the gene, the researchers found that they could restore siRNA control and thus prevent the transposons from jumping and show how the fungi develop drug resistance.

Although the gene segments responsible for coding for siRNAs are extremely small and difficult to find, RUB researcher Dr. Tim Dahlmann was able to locate them via bioinformatic analyses, the university added, noting that the discovery could be used for the treatment of fungal infections.

“We conclude that hypermutation and drug resistance in these clinical isolates result from RNA-interference loss and accumulation of Cnl1 elements,” the study read.