Siderophores; iron scavengers: the novel & promising targets for pathogen specific antifungal therapy

ABSTRACT

Introduction: 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.

KEYWORDS:

• Siderophore
• virulence
• homeostasis
• opportunistic
• trojan horse

Article highlights

• The conditions envisaged in vivo regarding iron uptake and assimilation act like nutritional immunity for the host while the fungal pathogens break this barrier by targeting diverse iron sources through the secretion of siderophores to scavenge the metal from host proteins.

• Immunotherapy via the use of host’s iron chelators alone or in combination with standard drugs, siderophore sequestering siderocalins and boosting of immune system through the administration of cytokines, neutrophils is being repurposed as adjunctive antifungal therapy.

• Siderophore biosynthesis and uptake pathways; well elucidated for major fungal opportunists discloses ideal pathogen specific targets and the inhibitors designed for the crucial enzymes involved have depicted positive results in vitro.

• Synthetic siderophore- nucleoside analog conjugates via the Trojan Horse Approach have been tested against Candida which depicted enhanced antifungal potential.

• ⁶⁸Ga-labeled siderophores, particularly ⁶⁸Ga -TAFC, have been found to possess a high potential to be used as fungal radiotracers and have shown effectiveness in an aspergillosis rat model.

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Declaration of interest

The authors wish to thank University Grant commission (UGC), India for the necessary support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper is not funded.