Whole-Genome Sequence Analysis of Candida glabrata Isolates from a Patient with Persistent Fungemia and Determination of the Molecular Mechanisms of Multidrug Resistance
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Published:2023-04-26
Issue:5
Volume:9
Page:515
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ISSN:2309-608X
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Container-title:Journal of Fungi
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language:en
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Short-container-title:JoF
Author:
Lim Ha Jin1ORCID, Choi Min Ji2, Byun Seung A.1, Won Eun Jeong13, Park Joo Heon1, Choi Yong Jun1, Choi Hyun-Jung1ORCID, Choi Hyun-Woo1, Kee Seung-Jung1ORCID, Kim Soo Hyun1, Shin Myung Geun1ORCID, Lee Seung Yeob45ORCID, Kim Mi-Na3ORCID, Shin Jong Hee1ORCID
Affiliation:
1. Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju 61469, Republic of Korea 2. Microbiological Analysis Team, Biometrology Group, Korea Research Institute of Standards and Science (KRISS), Daejeon 34113, Republic of Korea 3. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea 4. Department of Laboratory Medicine, Jeonbuk National University Medical School and Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea 5. Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
Abstract
Whole-genome sequencing (WGS) was used to determine the molecular mechanisms of multidrug resistance for 10 serial Candida glabrata bloodstream isolates obtained from a neutropenic patient during 82 days of amphotericin B (AMB) or echinocandin therapy. For WGS, a library was prepared and sequenced using a Nextera DNA Flex Kit (Illumina) and the MiseqDx (Illumina) instrument. All isolates harbored the same Msh2p substitution, V239L, associated with multilocus sequence type 7 and a Pdr1p substitution, L825P, that caused azole resistance. Of six isolates with increased AMB MICs (≥2 mg/L), three harboring the Erg6p A158fs mutation had AMB MICs ≥ 8 mg/L, and three harboring the Erg6p R314K, Erg3p G236D, or Erg3p F226fs mutation had AMB MICs of 2–3 mg/L. Four isolates harboring the Erg6p A158fs or R314K mutation had fluconazole MICs of 4–8 mg/L while the remaining six had fluconazole MICs ≥ 256 mg/L. Two isolates with micafungin MICs > 8 mg/L harbored Fks2p (I661_L662insF) and Fks1p (C499fs) mutations, while six isolates with micafungin MICs of 0.25–2 mg/L harbored an Fks2p K1357E substitution. Using WGS, we detected novel mechanisms of AMB and echinocandin resistance; we explored mechanisms that may explain the complex relationship between AMB and azole resistance.
Funder
National Research Foundation of Republic of Korea
Subject
Plant Science,Ecology, Evolution, Behavior and Systematics,Microbiology (medical)
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