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

Pythiosis is a life-threatening infectious disease caused by the oomycete Direct exposure to 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 However, one patient with an invasive infection recovered completely following treatment with terbinafine and itraconazole. Additionally, the drug target sterol biosynthetic enzymes have been identified in the oomycete It remains an open question whether is susceptible to the antifungal drugs and harbors any of the known drug target enzymes. Here, we determined the susceptibilities of terbinafine and itraconazole against 30 isolates of We also analyzed endogenous sterols and searched for genes encoding the sterol biosynthetic enzymes in the genomes of and related oomycetes. The susceptibility assay showed that the growth of each of the 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 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 In conclusion, possesses an incomplete sterol biosynthetic pathway. Resistance to antifungal drugs targeting enzymes in the ergosterol biosynthetic pathway in was due to modifications or losses of some of the genes encoding the drug target enzymes.