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Mechanisms of Resistance

Evolution of the Sterol Biosynthetic Pathway of Pythium insidiosum and Related Oomycetes Contributes to Antifungal Drug Resistance

Tassanee Lerksuthirat, Areeporn Sangcakul, Tassanee Lohnoo, Wanta Yingyong, Thidarat Rujirawat, Theerapong Krajaejun
Tassanee Lerksuthirat
aDepartment of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
bMolecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
cResearch Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Areeporn Sangcakul
aDepartment of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Tassanee Lohnoo
cResearch Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Wanta Yingyong
cResearch Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Thidarat Rujirawat
cResearch Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Theerapong Krajaejun
aDepartment of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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DOI: 10.1128/AAC.02352-16
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ABSTRACT

Pythiosis is a life-threatening infectious disease caused by the oomycete Pythium insidiosum. Direct exposure to Py. insidiosum zoospores can initiate infections of the eye, limb, gastrointestinal tract, or skin/subcutaneous tissue. Treatments for pythiosis have mostly relied on surgery. Antifungal drugs are generally ineffective against Py. insidiosum. However, one patient with an invasive Py. insidiosum infection recovered completely following treatment with terbinafine and itraconazole. Additionally, the drug target sterol biosynthetic enzymes have been identified in the oomycete Aphanomyces euteiches. It remains an open question whether Py. insidiosum is susceptible to the antifungal drugs and harbors any of the known drug target enzymes. Here, we determined the in vitro susceptibilities of terbinafine and itraconazole against 30 isolates of Py. insidiosum. We also analyzed endogenous sterols and searched for genes encoding the sterol biosynthetic enzymes in the genomes of Py. insidiosum and related oomycetes. The susceptibility assay showed that the growth of each of the Py. insidiosum isolates was inhibited by the antifungal agents, but only at difficult-to-achieve concentrations, which explains the clinical resistance of the drugs in the treatment of pythiosis patients. Genome searches of Py. insidiosum and related oomycetes demonstrated that these organisms contained an incomplete set of sterol biosynthetic enzymes. Gas chromatographic mass spectrometry did not detect any sterol end products in Py. insidiosum. In conclusion, Py. insidiosum possesses an incomplete sterol biosynthetic pathway. Resistance to antifungal drugs targeting enzymes in the ergosterol biosynthetic pathway in Py. insidiosum was due to modifications or losses of some of the genes encoding the drug target enzymes.

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Evolution of the Sterol Biosynthetic Pathway of Pythium insidiosum and Related Oomycetes Contributes to Antifungal Drug Resistance
Tassanee Lerksuthirat, Areeporn Sangcakul, Tassanee Lohnoo, Wanta Yingyong, Thidarat Rujirawat, Theerapong Krajaejun
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02352-16; DOI: 10.1128/AAC.02352-16

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Evolution of the Sterol Biosynthetic Pathway of Pythium insidiosum and Related Oomycetes Contributes to Antifungal Drug Resistance
Tassanee Lerksuthirat, Areeporn Sangcakul, Tassanee Lohnoo, Wanta Yingyong, Thidarat Rujirawat, Theerapong Krajaejun
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02352-16; DOI: 10.1128/AAC.02352-16
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KEYWORDS

antifungal agents
Drug Resistance, Fungal
Pythium
Sterols
Pythium insidiosum
pythiosis
sterol biosynthetic enzyme
in vitro susceptibility
evolution
antifungal drug

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