The rarity of clinical drug resistance to the antifungal amphotericin B is explained by the extreme costs that resistance mutations impose upon stress responses and virulence factors.

Highlights d A series of oxadiazoles were identified that ameliorate a-synuclein toxicity in yeast d Oxadiazoles directly inhibit yeast (Ole1) and human (SCD) stearoyl-CoA desaturases d Inhibiting Ole1 restored a-synuclein localization and reversed trafficking defects d Inhibiting SCD protected human neurons from a-synuclein toxicity Authors

Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. But this benefit often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report dramatically less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and bind their target (the fungal sterol, ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. Surprisingly, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.