28
siderophore- ampicillin and found to be effective against both the wild and mutant
strain of bacteria (Table 2.2) (Möllmann et al. 2009). Large number of drugs can be
conjugated where their transport can be made effective by membrane receptors and
pumping channels. Thus, THA can be exploited as novel approach to combat the
problem of resistance in fungal infections with less toxic implications.
2.5 Conclusion
The various strategies that can be exploited for the development of antifungal drugs
by targeting siderophore-mediated iron uptake system are enlisted in Table 2.1.
Enzymes employed in biosynthetic siderophore production are majorly focused,
and several studies pertaining to their characterization and inhibition are still in
preliminary phase, but further understanding would open the ventures for pathogenspecific and nontoxic antifungal formulations. The considerable difference in the
sequences of intermediary enzymes between host and pathogen helps in designing
pathogen-specific inhibitors (da Silva et al. 2002). The major enzyme involved in
siderophore synthesis is NMO which is found to be crucial for virulence. Analysis
of active site of enzymes using X-ray crystallography and in silico methods helps in
developing site-specific inhibitors. No compound is yet established to have credentials to be used at clinical level, but since the importance of targets in establishing
virulence of pathogen is well proven, so there is some hope to develop drugs targeting siderophore-mediated iron transport among fungal pathogens (Balhara et al.
2016). Further, metal complexes of siderophore also have potential in diagnostics as
radiotracer. Trojan horse approach (THA) was also found to have promising results
in the fungal infections caused by resistant strains. Hence, by exploiting these
approaches, more effective drugs in the near future will likely to flourish which can
solve the riddle of antimicrobial resistance in the world of medicine.
References
Albrecht-Gary AM, Blanc S, Rochel N et al (1994) Bacterial iron transport: coordination properties of pyoverdin PaA, a peptidic siderophore of Pseudomonas aeruginosa. Inorg Chem
33:6391–6402
Allen G, Bromley M, Kaye SJ et al (2011) Functional analysis of a mitochondrial phosphopantetheinyl transferase (PPTase) gene pptB in Aspergillus fumigatus. Fungal Genet Biol 48:456–464
Baakza A, Dave BP, Dube HC (2004) Chemical nature, ligand denticity and quantification of fungal siderophores. NISCAIR-CSIR 42:96–105
Balhara M, Ruhil S, Kumar M et al (2014) An anti-Aspergillus protein from Escherichia coli
DH 5α: putative inhibitor of siderophore biosynthesis in Aspergillus fumigatus. Mycoses
57:153–162
Balhara M, Chaudhary R, Ruhil S et al (2016) Siderophores; iron scavengers: the novel & promising targets for pathogen specific antifungal therapy. Expert Opin Ther Targets 20:1477–1489
S. Bhatia and S. Singh
siderophore- ampicillin and found to be effective against both the wild and mutant
strain of bacteria (Table 2.2) (Möllmann et al. 2009). Large number of drugs can be
conjugated where their transport can be made effective by membrane receptors and
pumping channels. Thus, THA can be exploited as novel approach to combat the
problem of resistance in fungal infections with less toxic implications.
2.5 Conclusion
The various strategies that can be exploited for the development of antifungal drugs
by targeting siderophore-mediated iron uptake system are enlisted in Table 2.1.
Enzymes employed in biosynthetic siderophore production are majorly focused,
and several studies pertaining to their characterization and inhibition are still in
preliminary phase, but further understanding would open the ventures for pathogenspecific and nontoxic antifungal formulations. The considerable difference in the
sequences of intermediary enzymes between host and pathogen helps in designing
pathogen-specific inhibitors (da Silva et al. 2002). The major enzyme involved in
siderophore synthesis is NMO which is found to be crucial for virulence. Analysis
of active site of enzymes using X-ray crystallography and in silico methods helps in
developing site-specific inhibitors. No compound is yet established to have credentials to be used at clinical level, but since the importance of targets in establishing
virulence of pathogen is well proven, so there is some hope to develop drugs targeting siderophore-mediated iron transport among fungal pathogens (Balhara et al.
2016). Further, metal complexes of siderophore also have potential in diagnostics as
radiotracer. Trojan horse approach (THA) was also found to have promising results
in the fungal infections caused by resistant strains. Hence, by exploiting these
approaches, more effective drugs in the near future will likely to flourish which can
solve the riddle of antimicrobial resistance in the world of medicine.
References
Albrecht-Gary AM, Blanc S, Rochel N et al (1994) Bacterial iron transport: coordination properties of pyoverdin PaA, a peptidic siderophore of Pseudomonas aeruginosa. Inorg Chem
33:6391–6402
Allen G, Bromley M, Kaye SJ et al (2011) Functional analysis of a mitochondrial phosphopantetheinyl transferase (PPTase) gene pptB in Aspergillus fumigatus. Fungal Genet Biol 48:456–464
Baakza A, Dave BP, Dube HC (2004) Chemical nature, ligand denticity and quantification of fungal siderophores. NISCAIR-CSIR 42:96–105
Balhara M, Ruhil S, Kumar M et al (2014) An anti-Aspergillus protein from Escherichia coli
DH 5α: putative inhibitor of siderophore biosynthesis in Aspergillus fumigatus. Mycoses
57:153–162
Balhara M, Chaudhary R, Ruhil S et al (2016) Siderophores; iron scavengers: the novel & promising targets for pathogen specific antifungal therapy. Expert Opin Ther Targets 20:1477–1489
S. Bhatia and S. Singh