Open AccessAntifungal Susceptibility Profiles and Drug Resistance Mechanisms of Clinical Lomentospora prolificans Isolates
Author(s) -
Yongqin Wu,
Nina T. Grossman,
Marissa Totten,
Warda Memon,
Anna Fitzgerald,
Chunmei Ying,
Sean X. Zhang
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00318-20
Subject(s) - posaconazole , terbinafine , micafungin , voriconazole , itraconazole , microbiology and biotechnology , amphotericin b , minimum inhibitory concentration , biology , drug resistance , antibiotics , medicine , antifungal
Lomentospora prolificans is an opportunistic fungal pathogen with low susceptibility to current antifungal drugs. Here, we tested the in vitro susceptibility of 8 drugs against 42 clinical L. prolificans isolates. All isolates showed high MICs to voriconazole (MIC 90 >16 μg/ml), itraconazole (MIC 90 >16 μg/ml), posaconazole (MIC 90 >16 μg/ml), isavuconazole (MIC 90 >16 μg/ml), amphotericin B (MIC 90 >16 μg/ml), and terbinafine (MIC 90 >64 μg/ml) and high minimum effective concentrations (MECs) to micafungin (MEC 90 >8 μg/ml), with the exception of miltefosine showing an MIC 90 value of 4 μg/ml. We examined six different in vitro drug combinations and found that the combination of voriconazole and terbinafine achieved the most synergistic effort against L. prolificans We then annotated the L. prolificans whole genome and located its Cyp51 and Fks1 genes. We completely sequenced the two genes to determine if any mutation would be related to azole and echinocandin resistance in L. prolificans We found no amino acid changes in Cyp51 protein and no tandem repeats in the 5' upstream region of the Cyp51 gene. However, we identified three intrinsic amino acid residues (G138S, M220I, and T289A) in the Cyp51 protein that were linked to azole resistance. Likewise, two intrinsic amino acid residues (F639Y, W695F) that have reported to confer echinocandin resistance were found in Fks1 hot spot regions. In addition, three new amino acid alterations (D440A, S634R, and H1245R) were found outside Fks1 hot spot regions, and their contributions to echinocandin resistance need future investigation. Overall, our findings support the notion that L. prolificans is intrinsically resistant to azoles and echinocandins.