Fungal infections are a major contributor to illness and death among people with weakened immune systems. In these patients, fungal infections caused by molds or fungi are complicated to treat due to limited drug classes and antifungal drug resistance. Sarah Beattie, PhD, assistant professor of pediatrics-infectious diseases, at University of Iowa Health Care, and her team, are using high-throughput drug screening against the most common disease-causing mold, Aspergillus fumigatus, to identify new treatments. Beattie and her team hope to improve treatments for fungal and invasive mold infections, moving toward a future in which treatments are safer and more effective for patients who urgently need them.
Targeting Fungal Vulnerabilities
To identify the most promising treatment options for A. fumigatus, Beattie and her team relied heavily on creativity and innovation, ultimately creating a new type of screening for molds.
“We developed a screening platform for HTS (high throughput screening) of A. fumigatus that does not detect fungal growth inhibition directly but detects damage to the fungal cells that occur when they break open,” Beattie explains. “It is a very sensitive test that not only identifies compounds that inhibit the growth of A. fumigatus, but also those that compromise its rigid cell wall.”
Beattie knew that the fungal cell wall is essential for fungal survival within a host and most importantly that the distinct structure of the cell wall is not present in human cells. Given the uniqueness of this structure to fungi, treatments that target the cell wall will likely have fewer side effects for patients compared to those that target conserved pathways between fungi and humans.
Using this knowledge, Beattie adapted a screening platform for use with mold species. This methodology was originally developed for the beverage industry to detect the lysis (breaking open) of yeast cells during brewing and has been previously adapted for high-throughput screens against yeast and bacteria. The novel application of this screen to molds has opened a new avenue to detect antifungal activity against these technically challenging organisms.
“This method enables us to identify compounds with a broad range of anti-fungal activity that would otherwise be missed with traditional growth-based screens,” Beattie says.
The Search for Solutions
Beattie and her team have screened 150,000 synthetic, drug-like compounds against A. fumigatus using their high-throughput screening method. They have identified about 100 candidate antifungal compounds that are being tested for antifungal activity against clinically important fungi, including several mold species.
Currently, her team is working with one promising compound to determine how exactly it inhibits the growth of fungi. They are also collaborating with medicinal chemist Damien Castor, PhD, to make related versions of this molecule with the goal of improving antifungal performance. These related compounds will be compared in a series of tests to identify the most promising candidates, the best of which will be tested as treatments in in vivo models of fungal diseases.
A Better Future
While getting a new drug into the clinic is still many years away, Beattie hopes her team will have identified a lead compound for pre-clinical testing within a few years.
In addition to developing the promising compounds identified in their initial screen against A. fumigatus, the researchers are also expanding their efforts to include other clinically significant mold species. One focus is on several aggressive pathogens that are often intrinsically resistant to multiple classes of antifungal drugs.
“We have begun screening our 150,000-compound library against Mucor spp. and are seeing very little overlap in compound activity between Aspergillus fumigatus and Mucor spp., Beattie says.
“These findings reinforce the importance of direct screening with mold pathogens, and open new avenues for identifying treatments against some of the most challenging fungal infections in the clinic.”
The Impact of ICTS
Beattie is a member of the Institute for Clinical and Translational Science (ICTS) K12 Scholars' Program, which supports the training of outstanding early-career researchers who seek a career in clinical and translational science.
“ICTS has been pivotal in my transition to an independent investigator. Aside from financial support, the program has provided a strong network of mentors and peers. Participation in the monthly K Club meetings has strengthened my grant writing skills and fostered relationships with clinical faculty whom I would otherwise not interact with,” Beattie notes. “Interactions between clinical researchers and basic scientists like me are critical to ensure that we remain focused on the areas with the greatest clinical need.”