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Nontoxic antimicrobials that evade drug resistance

Abstract

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.

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Figure 1: Synthesis of AmB urea derivatives.
Figure 2: Sterol extraction and binding capacities of AmB ureas.
Figure 3: Efficacy and toxicity of AmB ureas in mice.
Figure 4: Characterization of mechanisms and costs of resistance to AmB ureas.

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Acknowledgements

Portions of this work were supported by the US National Institutes of Health (R01GM080436, R01GM080436-S), the Howard Hughes Medical Institute (HHMI) and the Mathers Foundation. M.D.B. is an HHMI Early Career Scientist, and S.L. is an HHMI Investigator.

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Authors

Contributions

S.A.D. and M.D.B. conceived the study and oversaw design of synthesis, biophysical and several biological experiments. B.M.V., L.W. and S.L. designed resistance studies. D.R.A. designed mouse toxicity and efficacy studies. S.A.D. synthesized all of the compounds. B.M.V. executed all of the resistance studies. M.M.E. performed sterol binding and designed and performed cell toxicity assays. K.M. performed efficacy and toxicity studies in mice. S.A.D., B.M.V., S.L. and M.D.B. wrote the manuscript.

Corresponding authors

Correspondence to Susan Lindquist or Martin D Burke.

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Competing interests

The University of Illinois has filed patents on compounds and chemistry reported herein. These have been licensed to REVOLUTION Medicines, a company for which M.D.B. is a founder.

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Davis, S., Vincent, B., Endo, M. et al. Nontoxic antimicrobials that evade drug resistance. Nat Chem Biol 11, 481–487 (2015). https://doi.org/10.1038/nchembio.1821

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