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Nontoxic antimicrobials that evade drug resistance
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Journal Article
Nontoxic antimicrobials that evade drug resistance
2015
Overview
An amphotericin antifungal that is less toxic to human cells due to its increased capacity for binding the fungal ergosterol over the human cholesterol can still evade resistance mechanisms, challenging the resistance-toxicity yin-yang of antimicrobials.
Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, 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 markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they 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. To our surprise, 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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 45/70
/ 631/326
/ 64
/ 64/60
/ Amphotericin B - analogs & derivatives
/ Amphotericin B - chemical synthesis
/ Amphotericin B - pharmacology
/ Animals
/ Antifungal Agents - chemical synthesis
/ Antifungal Agents - pharmacology
/ Candida - growth & development
/ Cell Survival - drug effects
/ Drug Resistance, Fungal - drug effects
/ Epithelial Cells - drug effects
/ Humans
/ Mice
/ Microbial Viability - drug effects
/ Mutation
