Struggling student helps design synthetic polymers to fight fungal infections

Each year, more than 2 million people are affected by invasive fungal infections, often caused by Candida species and associated with high mortality rates. The development of new therapies is progressing very slowly. However, demand is increasing, especially as drug resistance becomes increasingly common.

An interdisciplinary research team led by Dr. Sascha Brunke from the Leibniz Institute for Natural Products and Infection Biology – Hans Knöll Institute (Leibniz-HKI) has now investigated the mode of action and therapeutic potential of synthetic polymers.

These long-chain chemical compounds mimic natural peptides and inhibit the growth of microorganisms. The exact mechanism of action was previously unknown. But the mystery has now been solved, thanks to the coronavirus pandemic.

From Australia to Jena

Sebastian Schäfer, a PhD researcher and chemistry PhD student working on the design of antifungal polymers in chemical engineering at the University of New South Wales (UNSW), was in Germany when Australia closed its borders due to the pandemic, preventing Schäfer from returning to UNSW.

But the biotechnologist made a virtue of necessity and temporarily transferred his research to the Leibniz-HKI in Jena, where he added a chemical facet to the department of microbial pathogenicity mechanisms and turned his attention to pathogenic fungi.

This has not only led to new research approaches, but also to a very fruitful collaboration between natural product researchers and infection biologists from Germany and Australia.

The unexpectedly formed team developed several synthetic polymers from the polyacrylamide family that showed high efficacy against Candida albicans, even against resistant strains. In particular, the polymer called LH, in combination with the drug caspofungin, proved extremely effective against the fungus and significantly improved the survival rate of infected mite larvae in laboratory tests.

In the study, now published in Nature CommunicationsThe team also discovered for the first time the exact mode of action of the compounds.

“Synthetic polymers attack fungal cells in several ways at once. They also use new target structures, which explains their effectiveness. This is where they differ from conventional antifungals, which only work in one way,” explains Raghav Vij, one of the study’s authors alongside Schäfer.

The compounds caused stress in the fungal cell and weakened it by preventing glycosylation on the cell surface. In this chemical process, sugar chains bind to proteins, which is important for cell stability and function. The polymers also damaged the walls and membranes of the fungal cells, causing them to die. In addition, the polymers helped immune cells destroy the fungal cells, as shown in interaction tests.

Hope for resistant mushrooms

“It is also remarkable that LH combined with antifungal agents did not lead to the development of resistance in C. albicans in the laboratory. This indicates that these combination therapies are not only more effective, but also more durable than previous therapies and may therefore lead to better therapeutic success,” Vij says.

Another advantage is that “the production of synthetic polymers is relatively inexpensive. In addition, they are stable and storable compared to conventional active compounds. In low-income countries in particular, they could therefore make a significant contribution to public health,” Brunke summarises.

But before this can be achieved, further research is still needed. “So far, the polymers have only been tested on insect models. It must first be investigated in detail whether humans also tolerate the new therapy,” Brunke emphasizes.

The structure of the developed polymers also needs to be optimized. “We don’t yet know exactly which molecular components of the polymers affect which parts of the fungus. The target molecule is still missing, so to speak,” Vij explains.

It is also important to determine whether polymers have harmful effects on humans or the environment. Nevertheless, the research results are already moving in the right direction and give hope for new effective therapeutic options.