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Chapter 27 : Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates

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Abstract:

The assimilation of ionic iron, especially iron (III) is made very difficult by its insolubility at physiological pH. Many microorganisms circumvent this problem of low iron bioavailability by synthesizing and excreting siderophores, iron chelators that solubilize and sequester iron. Under iron-stressed conditions, these iron complexes can be recognized by outer membrane receptors of the microorganism and then are transported through the cellular membrane via active transport. As indicated by the generalized trihydroxamate, the most effective siderophores contain multiple ligands that bind iron(III) in an octahedral complex with the iron binding sites in a particular orientation to minimize the entropic effects of separate ligands. Numerous siderophores possess antibiotic properties. These antibiotic siderophores, or sideromycins, defend against iron assimilation by foreign organisms. The Shanzer group has synthesized several nonnatural siderophores to map the surface of ferrichrome receptors. This work demonstrated that iron chelators have two domains of siderophore-receptor interactions. The first domain is the iron binding domain, which is very sensitive to structural modification, whereas the second domain consists of the linker to the iron binding moiety, which is more tolerant of modification. Many groups synthesized simple iron chelators such as catechols and hydroxamic acids that were conjugated to β-lactam antibiotics at the C-6 or C-7 position. Unlike natural siderophores which usually contain two or three bidentate ligands, these were the simplest siderophores, with only one bidentate ligand. These conjugates had excellent activities against gram-negative bacteria, even in cases where the initial drug could not permeate the cell membrane alone.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27

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Outer Membrane Proteins
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High-Performance Liquid Chromatography
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Figures

Image of FIGURE 1
FIGURE 1

Representative siderophores.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 2
FIGURE 2

Generalized trihydroxamate siderophore analog.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 3
FIGURE 3

Siderophore transport system. Reprinted from with permission from the publisher.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 4
FIGURE 4

Natural siderophore antibiotics.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 5
FIGURE 5

Desferroxamine and synthetic chelators for iron overload treatment.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 6
FIGURE 6

Natural mycobactins.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 7
FIGURE 7

Synthetic mycobactin analogs.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 8
FIGURE 8

FR401, a bis-catecholspermidine.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 9
FIGURE 9

Mechanism for the generation of 5-methylene furanone (MF).

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 10
FIGURE 10

Structure of 2,6-dithiocarboxylic acid.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 11
FIGURE 11

Structure of IC202C.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 12
FIGURE 12

Structure of DTPA (structure 26) and other iron chelators (structures 27 and 28).

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 13
FIGURE 13

Generalized structure of Shanzer's ferrichrome analogs.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 14
FIGURE 14

Synthetic siderophore antibiotics.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 15
FIGURE 15

Antibiotics containing siderophore components.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 16
FIGURE 16

Carbacephalosporin conjugates of siderophore components.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 17
FIGURE 17

Diamino acid-based bis- and tris-catecholates.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 18
FIGURE 18

Penicillin conjugates of bis-catecholates.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 19
FIGURE 19

Pyoverdine-ampicillin conjugates.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 20
FIGURE 20

Pyoverdine-quinoline antibiotic conjugates.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 21
FIGURE 21

Conjugates of desferroxamine and nalidixic acid (structure acid 43) and anthraquinone carboxylic acid (structure 44).

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 22
FIGURE 22

Trihydroxamic acid analog of rhodotorulic acid (structure 45) and rhodotorulic acid (structure 46).

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 23
FIGURE 23

Proposed redox-based drug release.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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Image of FIGURE 24
FIGURE 24

Drug conjugates of isocyanurate-based trihydroxamate.

Citation: Girijavallabhan V, Miller M. 2004. Therapeutic Uses of Iron(III) Chelators and Their Antimicrobial Conjugates, p 413-434. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch27
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References

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