Lee Keunsook K, Kubo Karen, Abdelaziz Jehan Abdelmoneim, Cunningham Iain, de Silva Dantas Alessandra, Chen Xiaolin, Okada Hiroki, Ohya Yoshikazu, Gow Neil A R
The Aberdeen Fungal Group, MRC Centre for Medical Mycology, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan.
Cell Surf. 2018 Sep;3:12-25. doi: 10.1016/j.tcsw.2018.09.001.
The rise of widespread antifungal resistance fuels the need to explore new classes of inhibitory molecules as potential novel inhibitors. Recently a plant natural product poacic acid (PA) was shown to inhibit β-1,3-glucan synthesis, and to have antifungal activity against a range of plant pathogens and against . As with the echinocandins, such as caspofungin, PA targets the synthesis of cell wall β-1,3-glucan and has potential utility in the treatment of medically important fungi. However, the antifungal activity of PA against human pathogenic species has not been explored and the precise mode of action of this compound is not understood. Here, we show that PA sensitivity is regulated by the calcineurin pathway and that susceptibility to PA varied significantly between species, but did not correlate with β-glucan synthase activity, cell wall β-glucan content or the sensitivity of the species to caspofungin. Strains with point mutations (S645Y or S645P) in the hotspot1 region of the β-1,3-glucan synthase subunit Fks1, had decreased sensitivity to caspofungin but increased sensitivity to PA. , , and were more sensitive to PA than , , , and . These observations suggest that there are significant differences in the mode of action of PA and caspofungin and that PA or PA analogues are not likely to have broad spectrum activity in the treatment of infections.
广泛存在的抗真菌耐药性的增加促使人们去探索新型抑制分子作为潜在的新型抑制剂。最近，一种植物天然产物波阿西酸（PA）被证明可抑制β-1,3-葡聚糖合成，并对多种植物病原体具有抗真菌活性。与棘白菌素类药物（如卡泊芬净）一样，PA靶向细胞壁β-1,3-葡聚糖的合成，在治疗医学上重要的真菌方面具有潜在用途。然而，PA对人类致病菌种的抗真菌活性尚未得到探索，且该化合物的确切作用模式尚不清楚。在此，我们表明PA敏感性受钙调神经磷酸酶途径调控，并且不同菌种对PA的敏感性差异显著，但与β-葡聚糖合酶活性、细胞壁β-葡聚糖含量或该菌种对卡泊芬净的敏感性无关。β-1,3-葡聚糖合酶亚基Fks1的热点1区域存在点突变（S645Y或S645P）的菌株对卡泊芬净的敏感性降低，但对PA的敏感性增加。酿酒酵母、白色念珠菌和近平滑念珠菌对PA的敏感性高于热带念珠菌、光滑念珠菌、克柔念珠菌和季也蒙念珠菌。这些观察结果表明，PA和卡泊芬净的作用模式存在显著差异，并且PA或PA类似物在治疗念珠菌感染时不太可能具有广谱活性。
