Nontoxic antimicrobials that evade drug resistance
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2016
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| Online Access: | http://hdl.handle.net/1721.1/105472 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1826188573566566400 |
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| author | Davis, Stephen A Endo, Matthew M Whitesell, Luke Marchillo, Karen Andes, David R Burke, Martin D Vincent, Benjamin Matteson Lindquist, Susan |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Davis, Stephen A Endo, Matthew M Whitesell, Luke Marchillo, Karen Andes, David R Burke, Martin D Vincent, Benjamin Matteson Lindquist, Susan |
| author_sort | Davis, Stephen A |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:01:46Z |
| format | Article |
| id | mit-1721.1/105472 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:01:46Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1054722022-09-30T01:49:05Z Nontoxic antimicrobials that evade drug resistance Davis, Stephen A Endo, Matthew M Whitesell, Luke Marchillo, Karen Andes, David R Burke, Martin D Vincent, Benjamin Matteson Lindquist, Susan Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Vincent, Benjamin Matteson Lindquist, Susan 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. National Institutes of Health (U.S.) (Grants R01GM080436 and R01GM080436-S) Howard Hughes Medical Institute G. Harold and Leila Y. Mathers Foundation 2016-11-30T15:57:47Z 2016-11-30T15:57:47Z 2015-04 2014-10 Article http://purl.org/eprint/type/JournalArticle 1552-4450 1552-4469 http://hdl.handle.net/1721.1/105472 Davis, Stephen A et al. “Nontoxic Antimicrobials That Evade Drug Resistance.” Nature Chemical Biology 11.7 (2015): 481–487. https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1038/nchembio.1821 Nature Chemical Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Davis, Stephen A Endo, Matthew M Whitesell, Luke Marchillo, Karen Andes, David R Burke, Martin D Vincent, Benjamin Matteson Lindquist, Susan Nontoxic antimicrobials that evade drug resistance |
| title | Nontoxic antimicrobials that evade drug resistance |
| title_full | Nontoxic antimicrobials that evade drug resistance |
| title_fullStr | Nontoxic antimicrobials that evade drug resistance |
| title_full_unstemmed | Nontoxic antimicrobials that evade drug resistance |
| title_short | Nontoxic antimicrobials that evade drug resistance |
| title_sort | nontoxic antimicrobials that evade drug resistance |
| url | http://hdl.handle.net/1721.1/105472 https://orcid.org/0000-0003-1307-882X |
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