Researcher explores mechanisms behind the antifungal resistant infections to find new curative therapeutics
José Vargas-Muñiz is the recipient of a National Institute of Health award to aid in finding treatments for fungal infections resistant to current treatments.
The fungus among us is becoming resistant to treatment, and one researcher wants to know why.
Virginia Tech researcher José Vargas-Muñiz recently received a five-year $2 million grant from the National Institute of Allergy and Infectious Diseases to better understand the role of the septins, a cytoskeleton protein, within the fungus Aspergillus fumigatus when exposed to the antifungal drug caspofungin.
“Gaining this knowledge can lead to novel fundamental advances that could ultimately be used to develop new therapeutics that improve caspofungin treatment outcomes in patients suffering from invasive aspergillosis,” said Vargas-Muñiz, assistant professor of biological sciences.
The National Institute of Allergy and Infectious Diseases is one of 27 research institutes and centers of the National Institutes of Health. The grant will bolster the work Vargas-Muñiz is already doing to understand the mechanisms at work within the fungal cell wall when it is exposed to the antifungal drug caspofungin.
“We notice this cytoskeleton component called septins, which are proteins, and when we remove one of them, the drug that is supposed to be static is now actually cidal. It’s killing the fungus,” said Vargas-Muñiz, who is an affiliate with the Fralin Life Sciences Institute. “There is about a 40 percent increase in the probability of survival for those infected in our model.”
Aspergillus fumigatus is an environmental fungus usually found in soil and compost heaps. A healthy immune system can stave off an infection, but those who are immunocompromised from certain types of cancers or organ transplants cannot. The first line of defense are azole antifungal drugs, which target the fungal plasma membrane.
According to Vargas-Muñiz, there is an increase in resistance to these drugs, similar to an increase in resistance to antibacterial drugs, and this leads to an approximate mortality rate of 30 to 90 percent for those infected.
“The Centers for Disease Control and Prevention added azole-resistant Aspergillus fumigatus to their watch list in their 2019 Antibiotic Resistance Threats in the United States report,” said Vargas-Muñiz, an affiliated faculty member with the molecular and cellular biology graduate program. “What they’re finding is that the fungicides they use in the fields are the same or similar to the ones they use in the clinics and this is contributing to the increase in resistance.”
Vargas-Muñiz also pointed out in his grant application that the economic impact from treating an invasive aspergillosis infection in the United States costs about $600 million each year and individual patients pay over $100,000 for treatment.
Caspofungin, which is the focus of Vargas-Muñiz’s project, is currently considered a second line of treatment. It targets the fungal cell wall, but against Aspergillus fumigatus the drug is fungistatic, which means it stops the growth but does not kill the fungus. And caspofungin fails to control infection in 50 percent of the treated patients.
Vargas-Muñiz has already conducted preliminary testing that indicates the potential for interventions to help the secondary drug become fungicidal and kill the fungus that causes the invasive aspergillosis.
“Getting new drugs approved is extremely hard, so learning to improve how we can use the ones already available is crucial in making timely progress in treating fungal infections,” said Rebecca Busch, a Ph.D. student in biological sciences who is working with Vargas-Muñiz in the lab.
They have all been collaborating with Laura Herring, the director of University of North Carolina Metabolomics and Proteomics Core Facility for the initial research. Their strong preliminary results and solid methodology are what helped Vargas-Muñiz win the award as they are key requirements listed on the National Institute of Allergy and Infectious Diseases website for R01 grant applications.
In addition to creating a more effective therapeutic drug against invasive aspergillosis, Vargas-Muñiz is looking to learn more about the mechanisms at work within the fungal cell wall when it is exposed to the antifungal drug caspofungin.
Vargas-Muñiz is not content to stop at just potentially improving the drug’s efficacy. He wants to delve further to understand what is actually happening with the septins, or proteins, when they are exposed to the antifungal drug.
“Completing this grant will close a critical gap in understanding how fungal pathogens respond to caspofungin and how septins facilitate this,” Vargas-Muñiz said. “With this knowledge, novel therapeutic approaches can be designed to improve the outcome of caspofungin treatment. These findings have a clear, direct translational potential.”
