Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B
The evolution of drug resistance in microbial pathogens provides a paradigm for investigating evolutionary dynamics with important consequences for human health. Candida albicans, the leading fungal pathogen of humans, rapidly evolves resistance to two major antifungal classes, the triazoles and ech...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/1721.1/83390 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1811082742168813568 |
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| author | Vincent, Benjamin Matteson Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Lindquist, Susan |
| author2 | move to dc.description.sponsorship |
| author_facet | move to dc.description.sponsorship Vincent, Benjamin Matteson Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Lindquist, Susan |
| author_sort | Vincent, Benjamin Matteson |
| collection | MIT |
| description | The evolution of drug resistance in microbial pathogens provides a paradigm for investigating evolutionary dynamics with important consequences for human health. Candida albicans, the leading fungal pathogen of humans, rapidly evolves resistance to two major antifungal classes, the triazoles and echinocandins. In contrast, resistance to the third major antifungal used in the clinic, amphotericin B (AmB), remains extremely rare despite 50 years of use as monotherapy. We sought to understand this long-standing evolutionary puzzle. We used whole genome sequencing of rare AmB-resistant clinical isolates as well as laboratory-evolved strains to identify and investigate mutations that confer AmB resistance in vitro. Resistance to AmB came at a great cost. Mutations that conferred resistance simultaneously created diverse stresses that required high levels of the molecular chaperone Hsp90 for survival, even in the absence of AmB. This requirement stemmed from severe internal stresses caused by the mutations, which drastically diminished tolerance to external stresses from the host. AmB-resistant mutants were hypersensitive to oxidative stress, febrile temperatures, and killing by neutrophils and also had defects in filamentation and tissue invasion. These strains were avirulent in a mouse infection model. Thus, the costs of evolving resistance to AmB limit the emergence of this phenotype in the clinic. Our work provides a vivid example of the ways in which conflicting selective pressures shape evolutionary trajectories and illustrates another mechanism by which the Hsp90 buffer potentiates the emergence of new phenotypes. Developing antibiotics that deliberately create such evolutionary constraints might offer a strategy for limiting the rapid emergence of drug resistance. |
| first_indexed | 2024-09-23T12:08:16Z |
| format | Article |
| id | mit-1721.1/83390 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:08:16Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/833902022-09-28T00:23:39Z Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B Vincent, Benjamin Matteson Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Lindquist, Susan move to dc.description.sponsorship Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Vincent, Benjamin Matteson Lindquist, Susan The evolution of drug resistance in microbial pathogens provides a paradigm for investigating evolutionary dynamics with important consequences for human health. Candida albicans, the leading fungal pathogen of humans, rapidly evolves resistance to two major antifungal classes, the triazoles and echinocandins. In contrast, resistance to the third major antifungal used in the clinic, amphotericin B (AmB), remains extremely rare despite 50 years of use as monotherapy. We sought to understand this long-standing evolutionary puzzle. We used whole genome sequencing of rare AmB-resistant clinical isolates as well as laboratory-evolved strains to identify and investigate mutations that confer AmB resistance in vitro. Resistance to AmB came at a great cost. Mutations that conferred resistance simultaneously created diverse stresses that required high levels of the molecular chaperone Hsp90 for survival, even in the absence of AmB. This requirement stemmed from severe internal stresses caused by the mutations, which drastically diminished tolerance to external stresses from the host. AmB-resistant mutants were hypersensitive to oxidative stress, febrile temperatures, and killing by neutrophils and also had defects in filamentation and tissue invasion. These strains were avirulent in a mouse infection model. Thus, the costs of evolving resistance to AmB limit the emergence of this phenotype in the clinic. Our work provides a vivid example of the ways in which conflicting selective pressures shape evolutionary trajectories and illustrates another mechanism by which the Hsp90 buffer potentiates the emergence of new phenotypes. Developing antibiotics that deliberately create such evolutionary constraints might offer a strategy for limiting the rapid emergence of drug resistance. National Science Foundation (U.S.). Graduate Research Fellowship Program Howard Hughes Medical Institute G. Harold and Leila Y. Mathers Foundation 2013-12-30T19:22:32Z 2013-12-30T19:22:32Z 2013-10 2013-02 Article http://purl.org/eprint/type/JournalArticle 1545-7885 1544-9173 http://hdl.handle.net/1721.1/83390 Vincent, Benjamin Matteson, Alex Kelvin Lancaster, Ruth Scherz-Shouval, Luke Whitesell, and Susan Lindquist. “Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B.” Edited by Aaron P. Mitchell. PLoS Biology 11, no. 10 (October 29, 2013): e1001692. https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1371/journal.pbio.1001692 PLoS Biology http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Vincent, Benjamin Matteson Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Lindquist, Susan Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B |
| title | Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B |
| title_full | Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B |
| title_fullStr | Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B |
| title_full_unstemmed | Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B |
| title_short | Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B |
| title_sort | fitness trade offs restrict the evolution of resistance to amphotericin b |
| url | http://hdl.handle.net/1721.1/83390 https://orcid.org/0000-0003-1307-882X |
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