135
trihydroxamate-ciprofloxacin conjugates and biscatecholate-monohydroxamate
mixed ligand siderophore-carbacephalosporin conjugates (Wencewicz and Miller
2013; Wencewicz et al. 2013). Several studies have shown that this kind of Trojan
horse strategy could overcome the antibiotic resistance in microorganisms
(Möllmann et al. 2009; Górska et al. 2014; Mislin and Schalk 2014). However,
resistance development may occur to the transport of siderophores into the microbial cell as it requires the availability of specific outer membrane receptors (TonB
receptors) and loss of these receptors may cause resistance to the entry of
siderophore- antibiotic conjugates (Ferguson et al. 2000; Górska et al. 2014).
However, more understanding of those receptors and siderophores is progressing
and it is anticipated that the emergence of resistance to siderophore conjugates may
be minimized. One of those approaches involved the usage of mixed siderophore
conjugates to target multiple receptors of iron transport (Wencewicz and Miller
2013; De Serrano 2017; Schalk 2018).
Fungal cells are mostly similar to mammalian cells with respect to the metabolic
processes concerned. Due to this property, the availability of selective and unique
antifungal therapeutic targets are limited. Recent evidence indicates that invasive
fungal infections are resistant to current pharmacotherapy and cause significant
mortality. Hence, the development of newer antifungal agents are required
(Szebesczyk et al. 2016; Wilson et al. 2016). Brumbagh et al. developed a vaccine
with siderophore receptor, yersiniabactin receptor (FYuA), in a murine model
against pyelonephritis (Brumbaugh et al. 2013). Recently, Smith et al. developed a
vaccine against urinary pathogenic bacteria Escherichia coli by using protein conjugates of yersiniabactin and aerobactin in a murine model (Smith et al. 2016).
8.3.4 Molecular Imaging
It is important to know the exact location of infection inside the human body for
appropriate treatment. The radioimaging with siderophores helps in this aspect by
giving the location of the microbial mass. Radionuclides such as gallium-68, zirconium- 89, copper-64 and scandium-44 are used in positron emission tomography
(PET) in clinical diagnostics. Attaching radiometals to the biomolecules requires a
chelator to be attached with stability and without compromising the binding affinity
to the target (Petrik et al. 2017). These molecular imaging molecules can be
synthesized via the exchange of iron and the introduction of suitable radiometal to
the natural (iron-)siderophore complex. Alternatively, a suitable chromophore can
be used to modify the natural siderophore for better optical imaging (Nudelman
et al. 1998; Ouchetto et al. 2005; Szebesczyk et al. 2016). Triacetylfusarinine C
(TAFC) was successfully radiolabelled with
68
Ga using few micrograms of siderophores and the complex exhibited high chemical stability (Helbok et al. 2010).
Several 68Ga-labelled siderophores exhibited excellent imaging properties.
However, only
68
Ga-TAFC and
68
Ga-ferrioxamine E were found to be suitable for
uptake by fungal cells in a culture with better pharmacokinetic and metabolic prop8 Chemistry and Biomedical Applications of Fungal Siderophores
trihydroxamate-ciprofloxacin conjugates and biscatecholate-monohydroxamate
mixed ligand siderophore-carbacephalosporin conjugates (Wencewicz and Miller
2013; Wencewicz et al. 2013). Several studies have shown that this kind of Trojan
horse strategy could overcome the antibiotic resistance in microorganisms
(Möllmann et al. 2009; Górska et al. 2014; Mislin and Schalk 2014). However,
resistance development may occur to the transport of siderophores into the microbial cell as it requires the availability of specific outer membrane receptors (TonB
receptors) and loss of these receptors may cause resistance to the entry of
siderophore- antibiotic conjugates (Ferguson et al. 2000; Górska et al. 2014).
However, more understanding of those receptors and siderophores is progressing
and it is anticipated that the emergence of resistance to siderophore conjugates may
be minimized. One of those approaches involved the usage of mixed siderophore
conjugates to target multiple receptors of iron transport (Wencewicz and Miller
2013; De Serrano 2017; Schalk 2018).
Fungal cells are mostly similar to mammalian cells with respect to the metabolic
processes concerned. Due to this property, the availability of selective and unique
antifungal therapeutic targets are limited. Recent evidence indicates that invasive
fungal infections are resistant to current pharmacotherapy and cause significant
mortality. Hence, the development of newer antifungal agents are required
(Szebesczyk et al. 2016; Wilson et al. 2016). Brumbagh et al. developed a vaccine
with siderophore receptor, yersiniabactin receptor (FYuA), in a murine model
against pyelonephritis (Brumbaugh et al. 2013). Recently, Smith et al. developed a
vaccine against urinary pathogenic bacteria Escherichia coli by using protein conjugates of yersiniabactin and aerobactin in a murine model (Smith et al. 2016).
8.3.4 Molecular Imaging
It is important to know the exact location of infection inside the human body for
appropriate treatment. The radioimaging with siderophores helps in this aspect by
giving the location of the microbial mass. Radionuclides such as gallium-68, zirconium- 89, copper-64 and scandium-44 are used in positron emission tomography
(PET) in clinical diagnostics. Attaching radiometals to the biomolecules requires a
chelator to be attached with stability and without compromising the binding affinity
to the target (Petrik et al. 2017). These molecular imaging molecules can be
synthesized via the exchange of iron and the introduction of suitable radiometal to
the natural (iron-)siderophore complex. Alternatively, a suitable chromophore can
be used to modify the natural siderophore for better optical imaging (Nudelman
et al. 1998; Ouchetto et al. 2005; Szebesczyk et al. 2016). Triacetylfusarinine C
(TAFC) was successfully radiolabelled with
68
Ga using few micrograms of siderophores and the complex exhibited high chemical stability (Helbok et al. 2010).
Several 68Ga-labelled siderophores exhibited excellent imaging properties.
However, only
68
Ga-TAFC and
68
Ga-ferrioxamine E were found to be suitable for
uptake by fungal cells in a culture with better pharmacokinetic and metabolic prop8 Chemistry and Biomedical Applications of Fungal Siderophores