The disease is also difficult to diagnose. "There's a lot of people who just don't know that these terrible fungal diseases exist," Busch said. "This is different; it's an invasive fungal infection and hard to diagnose unless the doctors already kind of know what they're looking for."

According to the authors, this pathogen carries the highest per-patient cost of any invasive fungal disease, costing the United States an estimated $1.3 billion per year.

Why current drugs often fail

Doctors have remarkably few weapons against fungi. "When it comes to antifungal drugs, there are very few options available compared to antibacterial drugs," Busch said. "We have hundreds of antibacterial drugs, and we have somewhere around 10 [antifungal drugs]. Once you get a strain of the fungus that's resistant, it's like, what else do we treat you with?"

The first-line treatments, a class of drugs called triazoles, can kill the pathogen — but because they are chemically similar to agricultural fungicides, resistance sometimes develops. The second-line treatments, echinocandins, stop the fungus from growing but do not kill it. In other words, they hold the line rather than win the war.

Finding the fungus's shield

With a goal of improving the efficacy of antifungal drugs, the researchers set out to understand the mechanism that renders echinocandins essentially ineffective.

Echinocandins attack the fungal cell wall — the rigid outer structure that protects the cell. Busch's team genetically modified the fungal pathogen by stripping it of proteins that regulate those cell walls. The goal was to identify which proteins are integral to the pathogen's defenses.

The approach worked. In both lab and animal tests, the echinocandin drug killed the genetically modified pathogen. This result demonstrates how those proteins prevent the drug from killing the fungus under normal circumstances, and it helped the researchers identify which protein is most responsible for the resistance.

Having found the weakness in their fungal opponent, the researchers are now strategizing more targeted attacks with echinocandins.

Groundwork, not a cure — yet

The findings are preliminary in an important sense: the experiments relied on genetically modifying the fungus, something clinicians cannot do inside a patient. What the study provides is a map of the resistance mechanism — a target that future drugs or drug combinations could exploit. Translating that laboratory insight into a clinical treatment will take further research.

Still, the researchers see the work as a turning point. "It lays the groundwork for the future," Busch said.

The study, "Deletion of core septin gene aspB in Aspergillus fumigatus results in fungicidal activity of caspofungin," was published in Molecular Biology of the Cell (DOI: 10.1091/mbc.e26-03-0151) by Rebecca Jean Busch et al.