If approved, synthetic compound could bolster shaky arsenal of antifungal drugs
The lifesaving, but toxic, drug Amphotericin B forms scaffold-like structures that kill fungal cells by wresting away molecules that stabilize their cell membranes.The antifungal Amphotericin B is an old and effective drug—it saved many COVID-19 patients whose compromised immune systems failed to stop secondary fungal infections. But it sometimes causes life-threatening kidney damage.
AmB is a large, complex compound that’s painstaking to make from scratch. But in 2015, Burke and his colleagues reported in. The machine allowed Burke’s team to quickly build and test AmB analogs, each with a slight tweak to its chemical structure, to see whether any had reduced toxicity. One initially promising compound, abbreviated AmBMU, was safer but ultimately proved less effective in animal studies. “We pushed the pendulum too far,” Burke says. “We got rid of the toxicity but lost potency.
They gained ideas on where tweaks to the molecule might speed up its action by studying high-resolution images of AmB binding to both ergosterol and cholesterol recently provided by Chad Rienstra’s group at the University of Wisconsin-Madison. “The atomic resolution models were really the key to zoom in and identify these very subtle differences,” says Corinne Soutar, a UIUC graduate student and the paper’s co-first author.
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