By targeting the bacteria in microbiomes, scientists can improve human gut health, bolster the hardiness of agricultural crops, and treat wastewater.
Bacteria aren’t the only members of microbiomes, though. Fungi are also present—but they’re difficult to selectively target like bacteria. In healthcare, finding effective treatments for fungal infections can be tricky because fungal cells closely resemble those of mammals.
Biomedical engineering researchers at the University of Wisconsin-Madison have uncovered a workaround for effectively manipulating the fungal members of microbiomes. Recent PhD graduate Kevin Stindt and Associate Professor Megan McClean outline their method in a paper in the journal mSystems.
“Targeting fungi is a fundamental capability we don’t really have to modify microbiomes, whether you care about it for biotechnology or you care about it for biomedicine,” says McClean, whose research group studies cellular signaling.
To uncover that capability, Stindt (PhD biophysics ’23) and McClean relied upon a process bacteria use to transfer genetic material called conjugation. Though conjugation, in which the organisms physically connect and pass DNA, typically occurs between bacteria, it can sometimes involve eukaryotes, such as in many genetically modified crops. Stindt, who calls this version “interdomain conjugation,” combined mutated strains of the common bacteria E. coli and the well-studied fungus Saccharomyces cerevisiae (baker’s or brewer’s yeast) to modulate the level of conjugation to fungi and then affect larger-scale population changes.
“I feel like it’s a very underexplored tool,” Stindt says of employing bacteria as genetic donors, “in terms of target range, which species could be recipients.”
After confirming that they could tune the level of conjugation by controlling the respective cell ratios, the researchers applied those methods to save a flagging yeast population and to kill off another using a CRISPR-Cas9 gene editing tool transferred via conjugation. Those demonstrations showed that they could induce enough conjugation to effect population-level changes.
“It would be nice to find the tools, the knobs either way, from an academic standpoint. But if it’s not going to be enough conjugation in an entire population to do anything meaningful, then you’re playing around in an abstract space,” says Stindt, who will be joining the biochemistry faculty at UW-Stevens Point in fall 2024.
The researchers have filed a patent for their work through the Wisconsin Alumni Research Foundation.
They’re now applying their techniques to clinically relevant fungal pathogens, such as Candida glabrata, and to fungi that form on implanted medical devices and other surfaces. Stindt also hopes to expand the number of fungal targets for biotechnology purposes, such as environmental remediation.
The two plan to continue collaborating as Stindt gets his own lab up and running in Stevens Point.
“I’m really excited about the potential for targeting fungal pathogens,” says McClean, “but I think there are a lot of different applications.”
This research was funded by the National Institute of General Medical Sciences (MIRA grant R35GM128873), the National Institute of Allergy and Infectious Diseases (grant R01AI154940), the Wisconsin Alumni Research Foundation (grant 135 AAI9593), the University of Wisconsin Carbone Cancer Center (support grant P30CA014520), and the National Institute of Health Molecular Biophysics Training Grant (T32GM130550).
Top photo caption: PhD student Kevin Stindt, left, and Associate Professor Megan McClean. Photo by: Tom Ziemer.