Desferrioxamine and desferrioxamine-caffeine as carriers of aluminum and gallium to microbes via the Trojan Horse Effect

Alvarado-Huayhuaz, Jesus Antonio; Vitorino, Hector Aguilar; Campos, Othon Souto; Serrano, Sı́lvia Helena Pires; Kaneko, Telma Mary; Espósito, Breno Pannia

doi:10.1016/j.jtemb.2017.01.006

Cited by 25 publications

(19 citation statements)

References 29 publications

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“…Mattos et al reported that Cd(II)/DFOB complex is a more efficient antimicrobial agent than the CdCl 2 salt [ 109 ]. Other studies on Al(III) and Ga(III) revealed that their complexes with DFOB (and DFOB-caffeine derivative) enhance or at least maintain the antimicrobial activity of free metal ions and free siderophore against Escherichia coli , P. aeruginosa , S. aureus and Candida albicans ; nonetheless, their biological activity requires further improvement for competitive application in the treatment of infections [ 110 ].…”

Section: Dfob In Medicinal Chemistry and Other Applicationsmentioning

confidence: 99%

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator

Bellotti

Remelli

2021

Molecules

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Deferoxamine B is an outstanding molecule which has been widely studied in the past decade for its ability to bind iron and many other metal ions. The versatility of this metal chelator makes it suitable for a number of medicinal and analytical applications, from the well-known iron chelation therapy to the most recent use in sensor devices. The three bidentate hydroxamic functional groups of deferoxamine B are the centerpiece of its metal binding ability, which allows the formation of stable complexes with many transition, lanthanoid and actinoid metal ions. In addition to the ferric ion, in fact, more than 20 different metal complexes of deferoxamine b have been characterized in terms of their chemical speciation in solution. In addition, the availability of a terminal amino group, most often not involved in complexation, opens the way to deferoxamine B modification and functionalization. This review aims to collect and summarize the available data concerning the complex-formation equilibria in solutions of deferoxamine B with different metal ions. A general overview of the progress of its applications over the past decade is also discussed, including the treatment of iron overload-associated diseases, its clinical use against cancer and neurodegenerative disorders and its role as a diagnostic tool.

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Section: Dfob In Medicinal Chemistry and Other Applicationsmentioning

confidence: 99%

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator

Bellotti

Remelli

2021

Molecules

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“…Unfortunately, in the clinic, the treatment of fungal infections using nystatin and amphotericin B has been hindered by the low selectivity of these molecules for the target cells versus the host cells, poor water solubility and, consequently, low absorption and bioavailability. , In this work, we showed that FsC could serve as an active targeting molecule for these pathogenic fungi (Figure and Figure ). Therefore, novel active targeting reagents, which may include targeted drug delivery systems, antimicrobial gallium ion carriers, ,, or antifungal “sideromycins”, can be designed and fabricated using FsC with some simple chemical methods …”

Section: Results and Discussionmentioning

confidence: 99%

“…Siderophore–antibiotic conjugates termed “sideromycins” can be actively taken up specifically by the siderophore transport systems of some bacteria, acting as “Trojan horses” . These “sideromycins” could significantly impair the development of resistance, could enhance antimicrobial activities, and may provide a valuable chemical tool for the strain-selective modulation of the microbiota. , Moreover, another type of siderophore-based “Trojan horse” without any conjugation to antibiotics has been prepared in the form of gallium (Ga 3+ ) ion-chelating siderophores, which could deliver the antimicrobial metal ion of Ga 3+ into the cells of Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , and Candida albicans ; this delivery is by the active absorption of the deferoxamine siderophore, which kills these pathogens by the disruption of their iron metabolisms. , The possession of native and foreign siderophore transporters on the cell membranes of these pathogens contributes to their active uptake of siderophores and consequently confers the active targeting abilities of siderophores toward these pathogens. ,,, …”

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confidence: 99%

“…7,8 Moreover, another type of siderophore-based "Trojan horse" without any conjugation to antibiotics has been prepared in the form of gallium (Ga 3+ ) ion-chelating siderophores, which could deliver the antimicrobial metal ion of Ga 3+9 into the cells of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans; this delivery is by the active absorption of the deferoxamine siderophore, which kills these pathogens by the disruption of their iron metabolisms. 9,10 The possession of native and foreign siderophore transporters on the cell membranes of these pathogens contributes to their active uptake of siderophores and consequently confers the active targeting abilities of siderophores toward these pathogens. 2,7,8,10 Fusarinine C (FsC), also known as "fusigen", is a hydroxamate siderophore.…”

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confidence: 99%

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Metabolic Rewiring Improves the Production of the Fungal Active Targeting Molecule Fusarinine C

Wang

et al. 2019

ACS Synth. Biol.

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Author: Recently, increasing research in siderophores has been dedicated to their possible medical applications in diagnostics and therapeutics for human pathogenic infections. Fusarinine C (FsC) is a natural hydroxamate siderophore that harbors three amino groups, which allow the easy chemical modification of FsC for the design of novel multifunctional conjugates. However, low production of FsC has hampered its extensive exploitation.Herein, we rewired the FsC biosynthetic pathway in the Aureobasidium melanogenum HN6.2 strain to achieve a self-supplying l-ornithine with component-simplified and enhanced production of extracellular siderophores, for which the FsC accounted for 94%, its final titer being approximately 1.7 g L–1. The convenient acquisition of FsC effectuated our exploitation for its application. We employed in vitro and in vivo assays to show that FsC is an active targeting molecule that acts on the human pathogenic fungi Trichophyton rubrum and Candida albicans; this demonstrates the potential to use FsC for the development of novel antifungal targeting reagents in the future.

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“…This drug is effective against P. nosoerga and is not known to date as being used for antibacterial monotherapy. By complexing with aluminum or gallium, deferoxamine has a Trojan horse effect, carrying these toxic metal ions into the bacterial metabolism [58] (Figure 3). Moreover, when used with ascorbic acid, deferoxamine showed a bacterial growth inhibiting effect [59], and added to gentamicin, this triple combination displayed a synergistic effect against some E. coli strains [60].…”

Section: Using Drug Associationsmentioning

confidence: 99%

In Vitro Screening of a 1280 FDA-Approved Drugs Library against Multidrug-Resistant and Extensively Drug-Resistant Bacteria

et al. 2022

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Alternative strategies against multidrug-resistant (MDR) bacterial infections are suggested to clinicians, such as drug repurposing, which uses rapidly available and marketed drugs. We gathered a collection of MDR bacteria from our hospital and performed a phenotypic high-throughput screening with a 1280 FDA-approved drug library. We used two Gram positive (Enterococcus faecium P5014 and Staphylococcus aureus P1943) and six Gram negative (Acinetobacter baumannii P1887, Klebsiella pneumoniae P9495, Pseudomonas aeruginosa P6540, Burkholderia multivorans P6539, Pandoraea nosoerga P8103, and Escherichia coli DSM105182 as the reference and control strain). The selected MDR strain panel carried resistance genes or displayed phenotypic resistance to last-line therapies such as carbapenems, vancomycin, or colistin. A total of 107 compounds from nine therapeutic classes inhibited >90% of the growth of the selected Gram negative and Gram positive bacteria at a drug concentration set at 10 µmol/L, and 7.5% were anticancer drugs. The common hit was the antiseptic chlorhexidine. The activity of niclosamide, carmofur, and auranofin was found against the selected methicillin-resistant S. aureus. Zidovudine was effective against colistin-resistant E. coli and carbapenem-resistant K. pneumoniae. Trifluridine, an antiviral, was effective against E. faecium. Deferoxamine mesylate inhibited the growth of XDR P. nosoerga. Drug repurposing by an in vitro screening of a drug library is a promising approach to identify effective drugs for specific bacteria.

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Desferrioxamine and desferrioxamine-caffeine as carriers of aluminum and gallium to microbes via the Trojan Horse Effect

Cited by 25 publications

References 29 publications

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator

Metabolic Rewiring Improves the Production of the Fungal Active Targeting Molecule Fusarinine C

In Vitro Screening of a 1280 FDA-Approved Drugs Library against Multidrug-Resistant and Extensively Drug-Resistant Bacteria

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