25
There are also few reports of natural siderophore-antibiotic complexes, viz.,
albomycins, ferrimycins, danomycins, and salmycins which are produced by
Streptomyces or Actinomyces. The albomycin complex is made of tris(N
5
-acetyl- N
5
-
hydroxyornithine) peptidal moiety which resembles functionalities of fungal siderophore (Table 2.2) (Pramanik et al. 2007). This moiety is having affinity for FhuA
receptor and FhuD binding protein, from where it is transported to cytoplasm by
ABC transporter which is located in the cell membrane. After entering into the cell
by a facilitated transport, the toxic component of albomycin displays the antimicrobial activity by preventing the protein synthesis through inhibition of aminoacyltRNA synthetase (Schauer et al. 2008).
Ferrimycin (Table 2.2) is found to be effective against Gram-positive bacteria,
particularly Staphylococcus aureus and Bacillus sp. Similarly, danomycins and
salmycins also have antimicrobial action. Apart from this many research groups
have synthesized artificial siderophores or conjugated antibiotics with wellestablished siderophores in order to modulate the pharmacokinetics of known drugs
(Braun et al. 2009). In this category, Malouin and coworkers investigated the potential of isocyanurate- and hydroxamate-based SDC against Candida spp. The combined drug was 13C-desketoneoenactin (DE) (Table 2.2); the addition of siderophore
and its concentration has positive effect on inhibitory action of drug (Bernier et al.
2005). This inhibitory activity is further increased to 16-fold when the conjugate
was tested on organism growing in iron-depleting medium. Further, the studies on
Candida albicans strain devoid of CaSit1/CaArn1 siderophore transporter protein
have shown no uptake of ferrichrome or the synthetic siderophore by the organism
for its growth promotion. It was also observed that the organism was less responsive
toward SDC as compared to its wild strain. Hence, the design of new synthetic siderophores which can be selectively transported through CaSit1/CaArn1 transporter
protein can be identified to improve/restore the activity of known drugs. In this
category, need for the exploration of novel drug-siderophore linkers also emerges
which can modulate the release of drug in desired concentration (Bernier et al. 2005).
Recently, Co(II) and Co(III) complexes of hydroxamate-based siderophores,
desferricrocin (DFR) and triacetylfusarinine (TAF) (Table 2.2), were synthesized
and investigated for their antifungal effect against solid stress agar cultures of
Penicillium brevicompactum and A. fumigates (Farkas et al. 2018). The complexes
of cobalt were found to be more stable in comparison to iron (III) complexes. Most
of the antifungal drugs develop resistance due to altered permeability across the cell
membrane, cell wall, and efflux of drugs by specialized pumps or reduce transport
by active transport proteins, etc. These resistance mechanisms can be bypassed if
mixed SDC will be synthesized and transported into the cell through different
uptake pathways. The advantage of this THA has led to the development of new
SDC which includes complexes of ciprofloxacin, ampicillin, amoxicillin, etc. (Ji
et al. 2012). Mollmann and coworkers have synthesized siderophore moieties based
on catechol framework. The metal-binding capacity of these moieties is analyzed by
performing chrome azurol S (CAS) assay. Several complexes of synthetic siderophore and aminopenicillin conjugates were synthesized and found to be effective
against P. aeruginosa infection. Compound 9924129 is one such conjugate of
2 Inhibition of Siderophores in Blocking Fungal Infection
There are also few reports of natural siderophore-antibiotic complexes, viz.,
albomycins, ferrimycins, danomycins, and salmycins which are produced by
Streptomyces or Actinomyces. The albomycin complex is made of tris(N
5
-acetyl- N
5
-
hydroxyornithine) peptidal moiety which resembles functionalities of fungal siderophore (Table 2.2) (Pramanik et al. 2007). This moiety is having affinity for FhuA
receptor and FhuD binding protein, from where it is transported to cytoplasm by
ABC transporter which is located in the cell membrane. After entering into the cell
by a facilitated transport, the toxic component of albomycin displays the antimicrobial activity by preventing the protein synthesis through inhibition of aminoacyltRNA synthetase (Schauer et al. 2008).
Ferrimycin (Table 2.2) is found to be effective against Gram-positive bacteria,
particularly Staphylococcus aureus and Bacillus sp. Similarly, danomycins and
salmycins also have antimicrobial action. Apart from this many research groups
have synthesized artificial siderophores or conjugated antibiotics with wellestablished siderophores in order to modulate the pharmacokinetics of known drugs
(Braun et al. 2009). In this category, Malouin and coworkers investigated the potential of isocyanurate- and hydroxamate-based SDC against Candida spp. The combined drug was 13C-desketoneoenactin (DE) (Table 2.2); the addition of siderophore
and its concentration has positive effect on inhibitory action of drug (Bernier et al.
2005). This inhibitory activity is further increased to 16-fold when the conjugate
was tested on organism growing in iron-depleting medium. Further, the studies on
Candida albicans strain devoid of CaSit1/CaArn1 siderophore transporter protein
have shown no uptake of ferrichrome or the synthetic siderophore by the organism
for its growth promotion. It was also observed that the organism was less responsive
toward SDC as compared to its wild strain. Hence, the design of new synthetic siderophores which can be selectively transported through CaSit1/CaArn1 transporter
protein can be identified to improve/restore the activity of known drugs. In this
category, need for the exploration of novel drug-siderophore linkers also emerges
which can modulate the release of drug in desired concentration (Bernier et al. 2005).
Recently, Co(II) and Co(III) complexes of hydroxamate-based siderophores,
desferricrocin (DFR) and triacetylfusarinine (TAF) (Table 2.2), were synthesized
and investigated for their antifungal effect against solid stress agar cultures of
Penicillium brevicompactum and A. fumigates (Farkas et al. 2018). The complexes
of cobalt were found to be more stable in comparison to iron (III) complexes. Most
of the antifungal drugs develop resistance due to altered permeability across the cell
membrane, cell wall, and efflux of drugs by specialized pumps or reduce transport
by active transport proteins, etc. These resistance mechanisms can be bypassed if
mixed SDC will be synthesized and transported into the cell through different
uptake pathways. The advantage of this THA has led to the development of new
SDC which includes complexes of ciprofloxacin, ampicillin, amoxicillin, etc. (Ji
et al. 2012). Mollmann and coworkers have synthesized siderophore moieties based
on catechol framework. The metal-binding capacity of these moieties is analyzed by
performing chrome azurol S (CAS) assay. Several complexes of synthetic siderophore and aminopenicillin conjugates were synthesized and found to be effective
against P. aeruginosa infection. Compound 9924129 is one such conjugate of
2 Inhibition of Siderophores in Blocking Fungal Infection