Article | Published:

Nontoxic antimicrobials that evade drug resistance

Nature Chemical Biology volume 11, pages 481487 (2015) | Download Citation

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.

  • Compound C48H77N3O16

    Amphotericin B methyl urea

  • Compound C49H80N4O16

    Amphotericin B aminoethyl urea

  • Compound C53H83N3O18

    Amphotericin B allyl 3-ureidopropanoate

  • Compound C50H79N3O18

    Amphotericin B ureidopropanoic acid

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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.

Author information

Affiliations

  1. Howard Hughes Medical Institute, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

    • Stephen A Davis
    • , Matthew M Endo
    •  & Martin D Burke
  2. Roger Adam Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

    • Stephen A Davis
    • , Matthew M Endo
    •  & Martin D Burke
  3. Microbiology Graduate Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Benjamin M Vincent
  4. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

    • Benjamin M Vincent
    • , Luke Whitesell
    •  & Susan Lindquist
  5. Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.

    • Karen Marchillo
    •  & David R Andes
  6. Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.

    • Karen Marchillo
    •  & David R Andes
  7. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Susan Lindquist

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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.

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.

Corresponding authors

Correspondence to Susan Lindquist or Martin D Burke.

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    Supplementary Results, Supplementary Table 1, Supplementary Figure 1 and Supplementary Note

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DOI

https://doi.org/10.1038/nchembio.1821

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