A new kind of antifungal drug acts a little like a siege tower, sidling up to the fortifications of infectious organisms, encouraging otherwise reluctant combatants to join the fight. Instead of a stone wall, the antifungal drug encounters the cell wall of a fungus. Instead of archers or spearmen, the drug rallies endogenous antibodies. Ultimately, drugs of this kind, which are called antibody-recruiting molecules targeting fungi (ARM-Fs), mediate engulfment and phagocytosis of the targeted organism. The castle, swarmed by antibodies, brought to the attention of immune cells, and beset on all sides, ultimately falls.

Details about the ARM-Fs appeared September 11 in the journal Angewandte Chemie, in an article entitled “Neutralization of Pathogenic Fungi with Small-Molecule Immunotherapeutics.” The article describes how a team of Yale scientists designed, synthesized, and evaluated the antifungal action of the ARM-Fs, which represent a new class of bifunctional molecule.

“Our approach relies on the use of non-peptidic small molecules, which selectively bind fungal cells and recruit endogenous antibodies to their surfaces, resulting in immune-mediated clearance,” wrote the article’s authors. “Using the opportunistic fungal pathogen Candida albicans as a model, we identified a highly specific bifunctional molecule able to mediate the engulfment and phagocytosis of C. albicans cells by human immune cells in biologically relevant functional assays.”

The discovery offers a potential new therapeutic approach to treating fungal illnesses that affect thousands of people each year, including patients whose immune systems are compromised by organ transplants, cancer treatment, and human immunodeficiency virus (HIV) infections.

“Because we're using the human immune system as the effector arm, this strategy is incredibly versatile,” said David Spiegel, M.D., the article’s senior author and a Yale chemistry and pharmacology professor. “It is the first time we've shown this strategy can work in treating a fungal disease.”

Over the past decade, Dr. Spiegel's laboratory has explored small-molecule approaches to treating a range of diseases, including cancer and HIV. Not only are such molecules effective against drug-resistant strains of diseases, Dr. Spiegel noted, they also may be used in combination with existing treatments.

“The possibility of a molecule like ours synergizing with existing fungal agents has tremendous potential,” Dr. Spiegel asserted.

“Systemic fungal infections represent an important public health concern, and new antifungal agents are highly desirable,” the Angewandte Chemie article stated. “This work represents a novel therapeutic approach to treating fungal illness with significant potential to complement and/or combine with existing treatment strategies.”

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