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Clearing the FoG: Antifungal tolerance is a subpopulation effect that is distinct from resistance and is associated with persistent candidemia

Alexander Rosenberg, Iuliana V. Ene, Maayan Bibi, Shiri Zakin, Ella Shtifman Segal, Naomi Ziv, Alon M. Dahan, Arnaldo L. Colombo, Richard J. Bennett, View ORCID ProfileJudith Berman
doi: https://doi.org/10.1101/206359
Alexander Rosenberg
School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv Israel
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Iuliana V. Ene
Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA
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Maayan Bibi
School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv Israel
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Shiri Zakin
School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv Israel
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Ella Shtifman Segal
School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv Israel
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Naomi Ziv
Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA, USA
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Alon M. Dahan
School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv Israel
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Arnaldo L. Colombo
Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
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Richard J. Bennett
Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA
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Judith Berman
School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv Israel
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  • ORCID record for Judith Berman
  • For correspondence: judithberman11@gmail.com
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Abstract

Drug susceptibility, defined by the minimal inhibitory concentration (MIC), often does not predict whether fungal infections will respond to therapy in the clinic. Tolerance at supra-MIC antifungal drug concentrations is rarely quantified and current clinical recommendations suggest it be ignored. Here, we measured and characterized drug-response variables that could influence the outcomes of fungal infections and be generalizable across major clades of Candida albicans, one of the most frequently isolated human fungal pathogens. We quantified antifungal tolerance as the fraction of growth (FoG) above the MIC and found that it is clearly distinct from susceptibility/resistance measured as MIC. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with the accumulation of intracellular drug. Importantly, many adjuvant drugs used together with fluconazole, a fungistatic drug, reduce tolerance without affecting resistance. These include inhibitors of major stress response hubs such as Hsp90, calcineurin, PKC1 and TOR. Accordingly, in an invertebrate infection model, adjuvant combination therapy was significantly more effective than fluconazole alone in treating highly tolerant isolates and did not improve the treatment of isolates with low tolerance levels. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia displayed significantly higher tolerance than isolates that were readily cleared by fluconazole. Thus, tolerance correlates with the response to fluconazole therapy in patients and may help predict whether infections will respond to fluconazole alone. Similarly, measuring tolerance may provide a useful clinical parameter for choosing appropriate therapeutic strategies to overcome persistent clinical candidemia.

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Posted March 02, 2018.
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Clearing the FoG: Antifungal tolerance is a subpopulation effect that is distinct from resistance and is associated with persistent candidemia
Alexander Rosenberg, Iuliana V. Ene, Maayan Bibi, Shiri Zakin, Ella Shtifman Segal, Naomi Ziv, Alon M. Dahan, Arnaldo L. Colombo, Richard J. Bennett, Judith Berman
bioRxiv 206359; doi: https://doi.org/10.1101/206359
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Clearing the FoG: Antifungal tolerance is a subpopulation effect that is distinct from resistance and is associated with persistent candidemia
Alexander Rosenberg, Iuliana V. Ene, Maayan Bibi, Shiri Zakin, Ella Shtifman Segal, Naomi Ziv, Alon M. Dahan, Arnaldo L. Colombo, Richard J. Bennett, Judith Berman
bioRxiv 206359; doi: https://doi.org/10.1101/206359

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