Synthetic peptides could one day thwart deadly infections wrought by opportunistic fungi. The molecules, which resemble innate immune molecules but consist of synthetic polymers, damaged key structures in the pathogenic fungi Candida albicans in a new study (1). Combined with another antifungal, the synthetic peptides protected human cells from infection, increased survival rates of a model species, and appeared to avoid evolving resistant fungal strains.
Many C. albicans infections are unpleasant but relatively innocuous, said Andrej Spec, a clinician and researcher specializing in pathogenic fungi at Washington University in St. Louis who was not associated with the study. These include conditions like thrush and skin fold infections, but if the immune system is compromised, these infections can become deadly. Patients who are on broad-spectrum antibiotics and are immunosuppressed are vulnerable to “deep and invasive” C. albicans infections, said Spec.
These infections can spread through the bloodstream or the gut. A recent analysis estimated that over four in 10 people who are hospitalized with C. albicans infections will die (2). Antifungal drugs are challenging to develop because, unlike bacteria or other microorganisms, fungi are eukaryotes — just like humans. “With bacteria, we often target their ribosomes,” said Spec. “Anything that kills a fungus at the ribosome level will kill us too.”
Existing drugs can also produce resistance in fungal populations, and clinicians often need to administer them intravenously, making long-term treatment challenging.
With bacteria, we often target their ribosomes. … Anything that kills a fungus at the ribosome level will kill us too.
- Andrej Spec, Washington University in St. Louis
Into this bleak picture comes a new collaboration between Australian and German research teams. Sascha Brunke, a microbiologist at the Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, explained that the researchers based its antifungal approach on antimicrobial peptides (AMPs), innate immune molecules deployed by many animal and microbial species (3). These are ancient and reliable defense mechanisms, but they are limited in their use as therapeutics because of their short half-life, fragility, and high manufacturing cost, said Brunke.
To circumvent these issues, Brunke and his colleagues developed synthetic polymers that mimicked AMP structure. They screened different polymers for their antifungal properties, settling on a structure called linear, heptyl (LH) that suppressed multiple C. albicans strains resistant to conventional antifungals. The polymer appeared to wreak havoc on the fungi’s cell membrane and proteins in their cell wall. “That's a good target because it is essentially the first contact that [the fungus] has with the human body,” said Brunke.
The team next tested how LH affected human vaginal epithelial cells infected with C. albicans by measuring the release of a damage marker called lactate dehydrogenase (LDH). On its own, the compound had unimpressive results. But in combination with the antifungal caspofungin, LH leveled up. The two compounds showed a huge synergistic effect. While cells treated with either compound alone saw at most a 20 percent reduction in LDH release, the polymer-caspofungin combination produced a 98 percent reduction.
The team tested how this fungi-unfriendly duo fared in a model of systemic C. albicans infection. In the model species — the greater wax moth, Galleria mellonella — LH and caspofungin increased survival when combined. An evolution assay suggested that while tolerant C. albicans strains could emerge when individual compounds were used, resistance to the combination treatment never appeared. Brunke pointed out that further research will be needed to establish whether resistance could evolve in clinical settings.
While the team has identified the pathways by which LH affects fungi, the region of the polymer responsible for its antifungal action is unclear, said Brunke. That would be an ideal next step, he added. “It would be interesting to find the real target so that we may even optimize the whole process.”
LH may find its greatest use as an adjunct treatment, concluded Brunke. “Maybe we can find other synergistic polymers that could also reduce the amount of classical antifungals that we need to give patients, which would reduce the toxic side effects of those antifungals.”
References
- Schaefer, S. et al. A synthetic peptide mimic kills Candida albicans and synergistically prevents infection. Nat Commun 15,6818 (2024).
- Mazi, P.B. et al. Attributable mortality of Candida bloodstream infections in the modern era: A propensity score analysis. Clin Infect Dis 75, 1031-1036 (2022).
- Huan, Y., Kong, Q., Mou H., & Yi, H. Antimicrobial peptides: Classification, design, application and research progress in multiple fields. Front Microbiol 11 (2020).
