Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes
ABSTRACT Antifungal drug tolerance is a response distinct from resistance, in which cells grow slowly above the MIC. Here, we found that the majority (69.2%) of 133 Candida albicans clinical isolates, including standard lab strain SC5314, exhibited temperature-enhanced tolerance at 37°C and 39°C, an...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-04-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00227-23 |
| _version_ | 1797839613929193472 |
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| author | Feng Yang Eduardo F. C. Scopel Hao Li Liu-liu Sun Nora Kawar Yong-bing Cao Yuan-Ying Jiang Judith Berman |
| author_facet | Feng Yang Eduardo F. C. Scopel Hao Li Liu-liu Sun Nora Kawar Yong-bing Cao Yuan-Ying Jiang Judith Berman |
| author_sort | Feng Yang |
| collection | DOAJ |
| description | ABSTRACT Antifungal drug tolerance is a response distinct from resistance, in which cells grow slowly above the MIC. Here, we found that the majority (69.2%) of 133 Candida albicans clinical isolates, including standard lab strain SC5314, exhibited temperature-enhanced tolerance at 37°C and 39°C, and were not tolerant at 30°C. Other isolates were either always tolerant (23.3%) or never tolerant (7.5%) at these three temperatures, suggesting that tolerance requires different physiological processes in different isolates. At supra-MIC fluconazole concentrations (8 to 128 μg/mL), tolerant colonies emerged rapidly at a frequency of ~10−3. In liquid passages over a broader range of fluconazole concentrations (0.25 to 128 μg/mL), tolerance emerged rapidly (within one passage) at supra-MICs. In contrast, resistance appeared at sub-MICs after 5 or more passages. Of 155 adaptors that evolved higher tolerance, all carried one of several recurrent aneuploid chromosomes, often including chromosome R, alone or in combination with other chromosomes. Furthermore, loss of these recurrent aneuploidies was associated with a loss of acquired tolerance, indicating that specific aneuploidies confer fluconazole tolerance. Thus, genetic background and physiology and the degree of drug stress (above or below the MIC) influence the evolutionary trajectories and dynamics with which antifungal drug resistance or tolerance emerges. IMPORTANCE Antifungal drug tolerance differs from drug resistance: tolerant cells grow slowly in drug, while resistant cells usually grow well, due to mutations in a few known genes. More than half of Candida albicans clinical isolates have higher tolerance at body temperature than they do at the lower temperatures used for most lab experiments. This implies that different isolates achieve drug tolerance via several cellular processes. When we evolved different strains at a range of high drug concentrations above inhibitory levels, tolerance emerged rapidly and at high frequency (one in 1,000 cells) while resistance appeared only later at very low drug concentrations. An extra copy of all or part of chromosome R was associated with tolerance, while point mutations or different aneuploidies were seen with resistance. Thus, genetic background and physiology, temperature, and drug concentration all influence how drug tolerance or resistance evolves. |
| first_indexed | 2024-04-09T16:00:51Z |
| format | Article |
| id | doaj.art-80d6195302b9458ea579b114577669b8 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-09T16:00:51Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
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| spelling | doaj.art-80d6195302b9458ea579b114577669b82023-04-25T13:04:56ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.00227-23Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid ChromosomesFeng Yang0Eduardo F. C. Scopel1Hao Li2Liu-liu Sun3Nora Kawar4Yong-bing Cao5Yuan-Ying Jiang6Judith Berman7Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaShmunis School of Biomedical and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, IsraelDepartment of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaShmunis School of Biomedical and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, IsraelDepartment of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaShmunis School of Biomedical and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, IsraelABSTRACT Antifungal drug tolerance is a response distinct from resistance, in which cells grow slowly above the MIC. Here, we found that the majority (69.2%) of 133 Candida albicans clinical isolates, including standard lab strain SC5314, exhibited temperature-enhanced tolerance at 37°C and 39°C, and were not tolerant at 30°C. Other isolates were either always tolerant (23.3%) or never tolerant (7.5%) at these three temperatures, suggesting that tolerance requires different physiological processes in different isolates. At supra-MIC fluconazole concentrations (8 to 128 μg/mL), tolerant colonies emerged rapidly at a frequency of ~10−3. In liquid passages over a broader range of fluconazole concentrations (0.25 to 128 μg/mL), tolerance emerged rapidly (within one passage) at supra-MICs. In contrast, resistance appeared at sub-MICs after 5 or more passages. Of 155 adaptors that evolved higher tolerance, all carried one of several recurrent aneuploid chromosomes, often including chromosome R, alone or in combination with other chromosomes. Furthermore, loss of these recurrent aneuploidies was associated with a loss of acquired tolerance, indicating that specific aneuploidies confer fluconazole tolerance. Thus, genetic background and physiology and the degree of drug stress (above or below the MIC) influence the evolutionary trajectories and dynamics with which antifungal drug resistance or tolerance emerges. IMPORTANCE Antifungal drug tolerance differs from drug resistance: tolerant cells grow slowly in drug, while resistant cells usually grow well, due to mutations in a few known genes. More than half of Candida albicans clinical isolates have higher tolerance at body temperature than they do at the lower temperatures used for most lab experiments. This implies that different isolates achieve drug tolerance via several cellular processes. When we evolved different strains at a range of high drug concentrations above inhibitory levels, tolerance emerged rapidly and at high frequency (one in 1,000 cells) while resistance appeared only later at very low drug concentrations. An extra copy of all or part of chromosome R was associated with tolerance, while point mutations or different aneuploidies were seen with resistance. Thus, genetic background and physiology, temperature, and drug concentration all influence how drug tolerance or resistance evolves.https://journals.asm.org/doi/10.1128/mbio.00227-23Candida albicansaneuploidyevolution of resistanceevolution of tolerancefluconazolephenotypic heterogeneity |
| spellingShingle | Feng Yang Eduardo F. C. Scopel Hao Li Liu-liu Sun Nora Kawar Yong-bing Cao Yuan-Ying Jiang Judith Berman Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes mBio Candida albicans aneuploidy evolution of resistance evolution of tolerance fluconazole phenotypic heterogeneity |
| title | Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes |
| title_full | Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes |
| title_fullStr | Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes |
| title_full_unstemmed | Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes |
| title_short | Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes |
| title_sort | antifungal tolerance and resistance emerge at distinct drug concentrations and rely upon different aneuploid chromosomes |
| topic | Candida albicans aneuploidy evolution of resistance evolution of tolerance fluconazole phenotypic heterogeneity |
| url | https://journals.asm.org/doi/10.1128/mbio.00227-23 |
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