Balhara Meenakshi, Chaudhary Renu, Ruhil Sonam, Singh Bharat, Dahiya Nisha, Parmar Virinder S, Jaiwal Pawan K, Chhillar Anil K
a Centre for Biotechnology , Maharshi Dayanand University , Rohtak , Haryana , India.
b Division of Epidemiology and Communicable Diseases , Indian Council of Medical Research , Delhi , India.
Expert Opin Ther Targets. 2016 Dec;20(12):1477-1489. doi: 10.1080/14728222.2016.1254196. Epub 2016 Nov 11.
The recent emergence of resistance, toxicity paradigm and limited efficacy of conventional antifungal drugs necessitate the identification of de novo targets in fungal metabolism. One of the most critical physiological processes during in vivo pathogenesis is maintenance of iron homeostasis. The most life threatening opportunistic human fungal pathogens like Aspergillus, Candida and Cryptococcus exploit the siderophore mediated iron uptake mechanism either for survival, virulence, propagation or resistance to oxidative stress envisaged in vivo during infection. Areas covered: In this review, we will highlight the metabolic pathways; specifically siderophore biosynthesis, uptake and utilisation, triggered in the fungal pathogens in iron starving conditions and the various putative targets viable in these pathways to be recruited as novel therapeutic antidotes either via biosynthetic enzymes catalytic site inhibitors or as drug conjugates through trojan horse approach and further role in the development of fungal specific reliable diagnostic markers. Expert opinion: Siderophores are the weapons released by a pathogen to conquer the battle for iron acquisition. Hence, the fungal siderophore biosynthetic pathways along with their uptake and utilisation mechanisms represent an ideal target for pathogen specific, host friendly therapeutic strategy which would block the proliferation of parasite without causing any harm to the mammalian host.
近期传统抗真菌药物出现耐药性、毒性问题且疗效有限，因此有必要在真菌代谢过程中寻找新的靶点。在体内致病过程中，最关键的生理过程之一是维持铁稳态。像曲霉属、念珠菌属和隐球菌属这类对人类生命威胁最大的机会性真菌病原体，在感染期间利用铁载体介导的铁摄取机制来生存、增强毒力、繁殖或抵抗体内设想的氧化应激。涵盖领域：在本综述中，我们将重点介绍真菌病原体在缺铁条件下引发的代谢途径，特别是铁载体的生物合成、摄取和利用，以及这些途径中可行的各种假定靶点，这些靶点可通过生物合成酶催化位点抑制剂或通过特洛伊木马方法作为药物偶联物被招募为新型治疗解毒剂，以及它们在开发真菌特异性可靠诊断标志物方面的进一步作用。专家观点：铁载体是病原体释放的用于夺取铁的武器。因此，真菌铁载体生物合成途径及其摄取和利用机制是病原体特异性、对宿主友好的治疗策略的理想靶点，该策略可阻止病原体增殖而不会对哺乳动物宿主造成任何伤害。
