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11.5.1 Siderophore–Drug Conjugates
Drug resistance is one of the major obstacles in the treatment strategies of most of
the microbial infections. In spite of overcoming drug resistance, the drug discovery
community has applied several approaches. One such approach is siderophoremediated drug delivery also known as ‘Trojan Horse strategy’. In this approach, the
drug conjugated with siderophore is administered to a patient with microbial infection. The presence of siderophore facilitates its (siderophore-drug complex) binding
with siderophore receptors and its transport across the cell membrane. Thus, the
drug is successfully delivered into the microbial cell. As this approach of drug delivery is more successful in the treatment strategies of bacterial infection (Wencewicz
et al. 2009), the same is also applied for fungal infections. The antifungal drug
13C-desketoneoenactin (DE) conjugated with siderophore was tested against various Candida sp. Results showed that the inhibitory activity of the siderophore-drug
conjugates has increased 16-fold than that of the drug alone and thus ensures the
success of the Trojan Horse strategy even for fungal diseases (Bernier et al. 2005).
The siderophore-nucleoside analogue conjugates were also studied and the results
showed an enhanced activity against Candida albicans (Balhara et al. 2016). The
siderophore transporter, CaSit1/CaArn1 of C. albicans, is associated with this
enhanced inhibition (Bernier et al. 2005).
11.5.2 Siderophore Mimics
As siderophores are crucially required for the survival of the pathogen in an iron
limiting environmental condition in its human host, when siderophore analogues are
designed as drugs and are administered, due to its structural resemblance, they
would be readily taken up by the pathogen. Hence, the siderophore analogues
(drugs) are easily transported across the fungal cell membrane, readily enter into the
cell and reach their site of action. Due to this, medicinal chemists have gained an
interest in designing and searching suitable siderophore analogues as potent antifungal agents.
In addition, the success of the siderophore-mediated drug delivery system
(Trojan Horse strategy) has raised an interest over the biologist towards synthesizing siderophores and its analogues as vehicles of the drugs. As mentioned earlier,
even though these techniques are focused with much interest for bacterial infections, a little focus has been started for fungal infections too.
VL-2397 is a cyclic hexapeptide and a natural compound isolated from the
Malaysian leaf litter fungus, Acremonium persicinium MF-347833. Due to its structural resemblance with siderophore ferrichrome, it is readily taken up by the fungal
cells via siderophore iron transporter 1 (Sit1) present in the cell membrane. This
drug is currently under clinical trial (Nakamura et al. 2017).
11 Siderophores in Antifungal Drug Discovery: A Computational Approach
11.5.1 Siderophore–Drug Conjugates
Drug resistance is one of the major obstacles in the treatment strategies of most of
the microbial infections. In spite of overcoming drug resistance, the drug discovery
community has applied several approaches. One such approach is siderophoremediated drug delivery also known as ‘Trojan Horse strategy’. In this approach, the
drug conjugated with siderophore is administered to a patient with microbial infection. The presence of siderophore facilitates its (siderophore-drug complex) binding
with siderophore receptors and its transport across the cell membrane. Thus, the
drug is successfully delivered into the microbial cell. As this approach of drug delivery is more successful in the treatment strategies of bacterial infection (Wencewicz
et al. 2009), the same is also applied for fungal infections. The antifungal drug
13C-desketoneoenactin (DE) conjugated with siderophore was tested against various Candida sp. Results showed that the inhibitory activity of the siderophore-drug
conjugates has increased 16-fold than that of the drug alone and thus ensures the
success of the Trojan Horse strategy even for fungal diseases (Bernier et al. 2005).
The siderophore-nucleoside analogue conjugates were also studied and the results
showed an enhanced activity against Candida albicans (Balhara et al. 2016). The
siderophore transporter, CaSit1/CaArn1 of C. albicans, is associated with this
enhanced inhibition (Bernier et al. 2005).
11.5.2 Siderophore Mimics
As siderophores are crucially required for the survival of the pathogen in an iron
limiting environmental condition in its human host, when siderophore analogues are
designed as drugs and are administered, due to its structural resemblance, they
would be readily taken up by the pathogen. Hence, the siderophore analogues
(drugs) are easily transported across the fungal cell membrane, readily enter into the
cell and reach their site of action. Due to this, medicinal chemists have gained an
interest in designing and searching suitable siderophore analogues as potent antifungal agents.
In addition, the success of the siderophore-mediated drug delivery system
(Trojan Horse strategy) has raised an interest over the biologist towards synthesizing siderophores and its analogues as vehicles of the drugs. As mentioned earlier,
even though these techniques are focused with much interest for bacterial infections, a little focus has been started for fungal infections too.
VL-2397 is a cyclic hexapeptide and a natural compound isolated from the
Malaysian leaf litter fungus, Acremonium persicinium MF-347833. Due to its structural resemblance with siderophore ferrichrome, it is readily taken up by the fungal
cells via siderophore iron transporter 1 (Sit1) present in the cell membrane. This
drug is currently under clinical trial (Nakamura et al. 2017).
11 Siderophores in Antifungal Drug Discovery: A Computational Approach