Novel Antifungal Strategies for Lethal Mucormycosis

描述(由申请人提供)：毛霉菌病是一种危及生命的感染，发生在因糖尿病酮症酸中毒、中性粒细胞减少症、皮质类固醇或器官移植而导致的免疫功能低下的患者。由于这些危险因素的流行率越来越高，这种致命感染的风险患者数量正在上升。尽管进行了毁容手术和积极的抗真菌治疗，毛霉菌病的死亡率仍然保持在50%，在播散性疾病或中性粒细胞减少症患者中接近100%。显然，迫切需要新的策略来预防和治疗毛霉病。在过去的十年里，新的治疗方法已经出现，有可能改善毛霉菌病的结果。最近，我们有了一个令人兴奋的发现，即铁螯合具有显著改善米根霉体内感染结局的潜力。此外，我们还发现死亡的稻瘟病菌能够介导对人类细胞的损伤，这表明稻瘟病菌中存在一种类似毒素的物质。新的数据表明，这种毒素很可能是由内共生细菌产生的，而不是真菌本身，针对这些内共生细菌的氟喹诺酮类药物可能被证明在治疗毛霉菌病方面有效。因此，假设联合治疗策略攻击真菌中至少两个不同的机械靶点将比目前标准的单一治疗方案产生更大的疗效。我们将在血源性播散型和吸入型小鼠毛霉病模型中确定最有效的抗真菌策略。主要终点将是死亡时间和组织真菌负担。药物的组织浓度将是次要终点。联合治疗的体外活性将被进行，以将易感性与生存结果相关联。这些特定的目标将确定针对小鼠高致死性毛霉病感染的最佳抗真菌策略。此外，从这些研究中获得的数据将为未来的R01奠定基础，这些R01旨在阐明真菌活性、铁代谢和毒素产生在这种感染的发病机制中的作用。最后，目前的研究结果将对优先考虑抗真菌策略和未来可能对感染这种极其致命的疾病的患者进行临床试验的研究设计至关重要。

DESCRIPTION (provided by applicant): Mucormycosis is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis, neutropenia, corticosteroids, or organ transplantation. Because of the increasing prevalence of these risk factors, the number of patients at risk for this deadly infection is on the rise. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >50%, and it approaches 100% in patients with disseminated disease or neutropenia. Clearly novel strategies to prevent and treat mucormycosis are urgently needed. In the past decade new therapies have become available that have the potential to improve outcomes of mucormycosis. Recently we have made the exciting discovery that iron chelation has the potential to markedly improve the outcome of Rhizopus oryzae infection in vivo. Furthermore, we have found that dead R. oryzae is capable of mediating damage to human cells, suggesting the presence of a toxin-like substance in R. oryzae. New data indicate that such a toxin is likely produced by an endosymbiotic bacteria rather than the fungus itself, and that fluoroquinolones targeting those endosymbiotic bacteria may prove efficacious in treating mucormycosis. It is therefore hypothesized that a combination therapeutic strategy that attacks at least two distinct mechanistic targets in the fungus will result in greater efficacy than the current standard monotherapy regimen. We will determine the maximally effective antifungal strategy in both a hematogenously disseminated and inhalational model of murine mucormycosis. The primary endpoint will be time to death, and tissue fungal burden. Tissue concentrations of the drugs will be secondary endpoints. The in vitro activity of the combination therapies will be performed to correlate susceptibility with survival outcomes. These Specific Aims will define the optimal antifungal strategy for highly lethal mucormycosis infections in mice. Additionally, data obtained from these studies will lay the foundation for future R01s designed to elucidate the role of fungal viability, iron metabolism, and toxin production in the pathogenesis of this infection. Finally, the results of the current studies will be crucial to prioritizing antifungal strategies and study design for possible future clinical trials of patients infected with this extraordinarily deadly disease.