Deferiprone iron chelation as a novel therapy for experimental mucormycosis
Deferiprone iron chelation as a novel therapy for experimental mucormycosis
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DOI：
10.1093/jac/dkl350
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发表时间：
2006-11-01
影响因子：
5.2
通讯作者：
Spellberg, Brad
中科院分区：
文献类型：
--
作者：
Ibrahim, Ashraf S.;Edwards, John E., Jr.;Spellberg, Brad
目的：已知使用铁络合剂去铁胺治疗的患者更易患毛霉病。然而，从人类宿主的角度来看，去铁胺是一种铁螯合剂，而去铁胺实际上是一个铁载体，将游离铁输送到引起毛霉病的米根霉。已经描述了其他铁螯合剂，包括去铁酮，它们不向稻曲霉输送铁。因此，我们试图确定去铁酮铁络合疗法是否能有效治疗毛霉病。方法：采用微量稀释法测定去铁酮铁络合剂对水稻青霉菌的体外MIC和最低杀菌浓度(MFC)。此外，我们还比较了去铁酮和脂质体两性霉素B(LAMB)治疗糖尿病酮症酸中毒小鼠毛霉病的疗效。结果：去铁酮在培养24 h时对稻瘟病菌表现出静态活性，而在孵育48 h时显示出杀灭作用。去铁酮在提高存活率和降低脑部真菌负担方面与羔羊一样有效，而且这两种药物在非铁超载动物身上都比安慰剂更有效。结论：铁络合物是治疗难治性毛霉菌感染的一种有前景的新的治疗策略。有必要进行进一步的研究，以评估联合抗真菌和铁络合疗法，以及评估其他铁络合剂的疗效。
Objectives: Patients treated with the iron chelator deferoxamine are known to be more susceptible to mucormycosis. However, while deferoxamine is an iron chelator from the perspective of the human host, deferoxamine actually serves as a siderophore, delivering free iron to Rhizopus oryzae, the major cause of mucormycosis. Other iron chelators, including deferiprone, which do not deliver iron to R. oryzae have been described. We therefore sought to determine whether iron-chelation therapy with deferiprone would effectively treat mucormycosis.Methods: In vitro MIC and minimum fungicidal concentration (MFC) of the iron chelator, deferiprone, for R. oryzae were determined by microdilution assay. In addition, we compared the efficacy of deferiprone with that of liposomal amphotericin B (LAmB) in treating mucormycosis in diabetic ketoacidotic mice.Results: Deferiprone demonstrated static activity against R. oryzae at 24 h, but showed cidality at 48 h of incubation. Deferiprone was as effective as LAmB at improving survival and decreasing brain fungal burden, and both drugs were more effective than placebo in non-iron-overloaded animals. Administration of free iron with deferiprone reversed protection, confirming that the mechanism of protection was iron chelation.Conclusions: Iron chelation is a promising, novel therapeutic strategy for refractory mucormycosis infections. Further studies are warranted to evaluate combination antifungal/iron chelation therapy and to evaluate the efficacy of other iron-chelating agents.