A structurally modified antifungal agent has shown reduced toxicity in mice and in human kidney cells while retaining its antimicrobial properties, according to a paper published in Nature. The advance could increase the clinical effectiveness and safety of such treatments in fighting deadly fungal infections.
Amphotericin B (AmB) is an antifungal agent produced by bacteria and has been used as a last line of defence against severe fungal infections for many decades. It achieves this by forming sponge-like aggregates that bind to a molecule known as ergosterol (which is found in bacterial and fungal cells and performs a similar function to mammalian cholesterol). This binding results in the extraction of ergosterol from the membrane, which leads to fungal cell death. Despite being effective, AmB is highly toxic in humans — particularly in renal cells. However, it is unknown whether this toxicity is due to the same mechanism that causes fungal cell death.
Arun Maji from the University of Illinois at Urbana-Champaign, Urbana, Illinois, U.S. and colleagues created analogues of AmB with changes to the parts of the molecule that bind sterols, with the aim of observing how these changes affected biological activity. These analogues were tested in human kidney cells, and it was determined that renal cell death was due to the binding and extraction of cholesterol from kidney cell membranes by AmB. The authors then designed a variant of AmB that can bind to and extract fungal ergosterol but not mammalian cholesterol, which would mitigate the toxic effects on the kidney. The resulting compound (which they named AM-2-19) was renal-sparing in human renal cells and in mice, while retaining high efficacy as an antifungal treatment. The treatment was also comparatively resilient to antimicrobial resistance.
This mechanism of action is conserved across many antifungal molecules, and the authors suggest that the technique could be used to reduce toxicity in additional drug treatments and thus increase their clinical efficacy. “Rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids,” the authors write.
