Laskaris Paris, Atrouni Ahmad, Calera José Antonio, d'Enfert Christophe, Munier-Lehmann Hélène, Cavaillon Jean-Marc, Latgé Jean-Paul, Ibrahim-Granet Oumaïma
Institut Pasteur, Cytokines & Inflammation, Département Infection & Epidemiology, Paris, France.
Universidad de Salamanca, Instituto de Biologia Funcional y Genómica, Departamento de Microbiología y Genética, Salamanca, Spain.
Antimicrob Agents Chemother. 2016 Sep 23;60(10):5631-9. doi: 10.1128/AAC.00324-16. Print 2016 Oct.
Aspergillus fumigatus can infect immunocompromised patients, leading to high mortality rates due to the lack of reliable treatment options. This pathogen requires uptake of zinc from host tissues in order to successfully grow and cause virulence. Reducing the availability of that micronutrient could help treat A. fumigatus infections. In this study, we examined the in vitro effects of seven chelators using a bioluminescent strain of A. fumigatus 1,10-Phenanthroline and N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) proved to be the chelators most effective at inhibiting fungal growth. Intraperitoneal administration of either phenanthroline or TPEN resulted in a significant improvement in survival and decrease of weight loss and fungal burden for immunosuppressed mice intranasally infected with A. fumigatus In vitro both chelators had an indifferent effect when employed in combination with caspofungin. The use of TPEN in combination with caspofungin also significantly increased survival compared to that when using these drugs individually. Our results suggest that zinc chelation may be a valid strategy for dealing with A. fumigatus infections and that both phenanthroline and TPEN could potentially be used either independently or in combination with caspofungin, indicating that their use in combination with other antifungal treatments might also be applicable.
烟曲霉可感染免疫功能低下的患者,由于缺乏可靠的治疗选择,导致死亡率很高。这种病原体需要从宿主组织中摄取锌才能成功生长并产生毒性。减少这种微量营养素的可利用性可能有助于治疗烟曲霉感染。在本研究中,我们使用一株烟曲霉的生物发光菌株检测了七种螯合剂的体外作用。1,10-菲咯啉和N,N,N',N'-四(2-吡啶甲基)乙二胺(TPEN)被证明是抑制真菌生长最有效的螯合剂。对经鼻感染烟曲霉的免疫抑制小鼠腹腔注射菲咯啉或TPEN,可显著提高生存率,减轻体重减轻和真菌负荷。在体外,这两种螯合剂与卡泊芬净联合使用时效果不佳。与单独使用这些药物相比,TPEN与卡泊芬净联合使用也显著提高了生存率。我们的结果表明,锌螯合可能是应对烟曲霉感染的一种有效策略,菲咯啉和TPEN都有可能单独使用或与卡泊芬净联合使用,这表明它们与其他抗真菌治疗联合使用也可能适用。