Selective antifungal outperformed amphotericin B in mice without kidney injury

A newly engineered antifungal called mandimycin M16 selectively recognized a structural feature of fungal ergosterol and neutralized 11 priority fungal pathogens in laboratory tests, according to a peer-reviewed study in Science Translational Medicine. The compound also outperformed amphotericin B in several mouse models of systemic Candida infection without causing the kidney injury observed with the established drug. These findings are preclinical and do not establish safety or efficacy in humans.

Amphotericin B has been used for more than 50 years and is considered a standard treatment for a wide range of fungal pathogens. Its clinical utility is constrained by toxic effects involving the kidneys and blood. The source release said these effects arise because the drug targets ergosterol, a compound in fungal membranes that shares many structural features with mammalian cholesterol. As a result, amphotericin B can disrupt cholesterol biology, complicating the separation of antifungal activity from host toxicity.

Wei Liu and colleagues addressed that problem by designing M16 around a molecular framework they called a 5+1 polyene scaffold. The scaffold enables the compound to target ergosterol through its C5-C8 diene system, a feature absent from cholesterol. In vitro, M16 neutralized 11 priority-threat fungal pathogens, including multidrug-resistant strains, without binding to cholesterol. The researchers said this selectivity could uncouple antifungal potency from disruption of host cholesterol biology, although the experiments do not show that M16 avoids every toxic effect associated with current therapies.

The investigators next tested M16 in several mouse models of systemic Candida infection. In those models, M16 outperformed amphotericin B and did not cause the kidney injury observed with the comparison treatment. The study therefore provides preclinical evidence that a compound engineered to recognize a fungal-specific sterol configuration can retain activity while reducing a major toxicity in the tested animal models. The authors described M16 as a mechanistic and structural foundation for designing next-generation antifungal drugs that could address therapeutic gaps left by current treatments, but further research would be needed to determine whether that design produces clinical benefits in patients.

Subject of Research: Preferential targeting of fungal ergosterol by mandimycin M16 in laboratory and mouse infection models

Article Title: New architecture for antifungal drug precisely combats fungal infections in mice without the usual toxicity

Article References: New architecture for antifungal drug precisely combats fungal infections in mice without the usual toxicity. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: mandimycin M16, antifungal drugs, ergosterol, Candida infections, mouse models, amphotericin B, drug toxicity, polyene scaffold, fungal pathogens, architecture, antifungal, drug