Lerksuthirat Tassanee, Sangcakul Areeporn, Lohnoo Tassanee, Yingyong Wanta, Rujirawat Thidarat, Krajaejun Theerapong
Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand.
Antimicrob Agents Chemother. 2017 Mar 24;61(4). doi: 10.1128/AAC.02352-16. Print 2017 Apr.
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.
腐皮病是一种由卵菌引起的危及生命的传染病。直接接触游动孢子可引发眼部、肢体、胃肠道或皮肤/皮下组织的感染。腐皮病的治疗大多依赖手术。抗真菌药物通常对其无效。然而，一名侵袭性感染患者在接受特比萘芬和伊曲康唑治疗后完全康复。此外，已在卵菌中鉴定出药物靶标甾醇生物合成酶。腐皮病菌是否对抗真菌药物敏感以及是否含有任何已知的药物靶标酶仍是一个悬而未决的问题。在此，我们测定了特比萘芬和伊曲康唑对30株腐皮病菌分离株的敏感性。我们还分析了内源性甾醇，并在腐皮病菌和相关卵菌的基因组中搜索编码甾醇生物合成酶的基因。敏感性试验表明，每种分离株的生长均受到抗真菌剂的抑制，但仅在难以达到的浓度下，这解释了这些药物在治疗腐皮病患者时的临床耐药性。对腐皮病菌和相关卵菌的基因组搜索表明，这些生物体含有一套不完整的甾醇生物合成酶。气相色谱 - 质谱法未在腐皮病菌中检测到任何甾醇终产物。总之，腐皮病菌具有不完整的甾醇生物合成途径。腐皮病菌对靶向麦角甾醇生物合成途径中酶的抗真菌药物的耐药性是由于一些编码药物靶标酶的基因发生了修饰或缺失。
