Steering the Immune Defense against Fungal Pathogens
Neutralization of pathogenic fungi with small-molecule immunotherapeutics
fungal infections represent an increasing health crisis, especially for immune-deficient patients. Scientists report that specific help could be provided by small-molecule immunotherapeutics with novel mechanism of action. They developed small bifunctional molecules that simultaneously bind both chitin, a specific feature of the fungal cell wall and a molecule not found in humans, and naturally occurring human antibodies and redirect the human immune system to eliminate fungal pathogens.
© Wiley-VCH
The fungal cell wall is an attractive target for the development of new antifungal drugs because many fungal cell-wall components are not present in humans, enabling exclusive targeting of fungal cells. To obtain the bifunctional molecules called Antibody-Recruiting Molecules targeting Fungi (ARM-F), the Spiegel Research Group at Yale University, USA, modified the key molecule calcofluor-white, a chitin-specific dye used to stain cell walls of fungi, and linked this molecule to a dinitrophenyl (DNP) group. DNP is recognized by human anti-DNP antibodies, which are naturally present in the bloodstream. The resulting chitin, ARM-F, and anti-DNP antibody complex formed is immunogenic and can stimulate effector immune cells, which then mediate the destruction of chitin-expressing fungal cells through phagocytosis.
The team was able to show that ARM-F can bind the model fungal pathogen Candida albicans and recruit anti-DNP antibodies in a dose-dependent manner, without compromising the viability of the cells. They went on to demonstrate that ARM-F has synergistic effects with the antifungal agent caspofungin—a type of echinocandin. Echinocandin-resistant fungi exhibit increased chitin production in the fungal cell wall; thus, the efficacy of ARM-F was even more pronounced when combined with caspofungin. In vitro studies confirmed that phagocytosis of fungal cells by human effector immune cells was increased in the presence of ARM-F.
The specific chitin-targeting mechanism of ARM-F holds promise for fighting echinocandin-resistant fungi, as well as a number of pathogenic fungi. These mechanistically novel small molecules have the potential of serving as an innovative platform for antifungal drug development, both as a single agent or for use in combination with existing antifungal strategies.
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