An Improved Stereocontrolled Synthesis of Pyochelin, Siderophore of Pseudomonas aeruginosa and Burkholderia cepacia

Zamri, Adel; Abdallah, Mohamed Abou-Elwafa

doi:10.1016/s0040-4020(99)00946-1

Cited by 64 publications

(56 citation statements)

References 25 publications

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“…The four other diastereoisomers, NeoPchI/II and ENeoPchI/II, have so far never been isolated from any siderophore-producing strain. In the presence of a metal ion, PchII isomerizes into PchI (24,36), and NeoPchII isomerizes into NeoPchI. This suggests a metal-driven template effect giving a cis H2Љ-H4Љ relationship that is necessary for optimal ferric ion tetracoordination by the siderophore.…”

Section: Discussionmentioning

confidence: 99%

“…Chemicals-Pch, neopyochelin (NeoPch), and EPch were synthesized and purified according to previously published protocols (23,24). Carbenicillin disodium salt was provided from Euromedex.…”

Section: Methodsmentioning

confidence: 99%

“…In the presence of this compound, the siderophore outer membrane transporter is still able to bind its ferrisiderophore, but the TonB machinery and, therefore iron uptake, is inhibited. The Pch stereoisomers used for these experiments were synthesized and purified as reported previously (23,24). The purification procedure used did not separate the diastereoisomer couples.…”

Section: Binding Of Pch Diastereoisomers Tomentioning

confidence: 99%

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Stereospecificity of the Siderophore Pyochelin Outer Membrane Transporters in Fluorescent Pseudomonads

Hoegy

Lee

Noël

et al. 2009

Journal of Biological Chemistry

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Pyochelin (Pch) and enantio-pyochelin (EPch) are enantiomer siderophores that are produced by Pseudomonas aeruginosa and Pseudomonas fluorescens, respectively, under iron limitation. Pch promotes growth of P. aeruginosa when iron is scarce, and EPch carries out the same biological function in P. fluorescens. However, the two siderophores are unable to promote growth in the heterologous species, indicating that siderophore-mediated iron uptake is highly stereospecific. In the present work, using binding and iron uptake assays, we found that FptA, the Fe-Pch outer membrane transporter of P. aeruginosa, recognized (K d ‫؍‬ 2.5 ؎ 1.1 nM) and transported Fe-Pch but did not interact with Fe-EPch. Likewise, FetA, the Fe-EPch receptor of P. fluorescens, was specific for Fe-EPch (K d ‫؍‬ 3.7 ؎ 2.1 nM) but did not bind and transport Fe-Pch. Growth promotion experiments performed under iron-limiting conditions confirmed that FptA and FetA are highly specific for Pch and EPch, respectively. When fptA and fetA along with adjacent transport genes involved in siderophore uptake were swapped between the two bacterial species, P. aeruginosa became able to utilize Fe-EPch as an iron source, and P. fluorescens was able to grow with Fe-Pch. Docking experiments using the FptA structure and binding assays showed that the stereospecificity of Pch recognition by FptA was mostly due to the configuration of the siderophore chiral centers C4؆ and C2؆ and was only weakly dependent on the configuration of the C4 carbon atom. Together, these findings increase our understanding of the stereospecific interaction between Pch and its outer membrane receptor FptA.To access iron, aerobic bacteria produce siderophores which form complexes with Fe 3ϩ in the environment and deliver it via specific membrane transporters to the bacteria (1). The energy required for this process is provided by the proton motive force of the inner membrane by means of an inner membrane complex comprising TonB, ExbB, and ExbD (2, 3). Pyochelin (Pch), 2 which is the focus of this study, is produced as a secondary siderophore under iron limitation by almost all strains of Pseudomonas aeruginosa and some closely related bacteria (4 -7). In pseudomonads, secondary siderophores (pyochelin, thioquinolobactin, etc.) are usually produced in smaller amounts, demonstrate lower iron affinity, and are rather simple molecules compared with pyoverdin (the main siderophore). It is hypothesized that under certain environmental or physiological conditions, secondary siderophores provide sufficient iron to the cell or fulfill functions other than iron sequestration (8). Pch was isolated for the first time from P. aeruginosa ATCC 15692 by Liu and Shokrani (9), and its structure was established later by Cox et al. (10) as (4ЈR,2ЉR,4ЉR)-2Ј-(2-hydroxyphenyl)-3Љ-methyl-4Ј,5Ј,2Љ,3Љ,4Љ,5Љ-hexahydro-[4Ј,2Љ]bithiazolyl-4Љ-carboxylic acid with three chiral centers located at C4Ј, C2Љ, and C4Љ (see Fig. 1). Pch is synthesized by P. aeruginosa from salicylate and two molecules of cysteine via a thiot...

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Section: Discussionmentioning

confidence: 99%

“…Chemicals-Pch, neopyochelin (NeoPch), and EPch were synthesized and purified according to previously published protocols (23,24). Carbenicillin disodium salt was provided from Euromedex.…”

Section: Methodsmentioning

confidence: 99%

Section: Binding Of Pch Diastereoisomers Tomentioning

confidence: 99%

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Stereospecificity of the Siderophore Pyochelin Outer Membrane Transporters in Fluorescent Pseudomonads

Hoegy

Lee

Noël

et al. 2009

Journal of Biological Chemistry

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“…Synthesis and Purification of Pyochelin, Neopyochelin, and Enantio-pyochelin-Pyochelin and neopyochelin were synthesized using protocols published previously (44,45). The synthesis of enantio-pyochelin was inspired by the same protocol and started with the condensation of 2-hydroxybenzonitrile with L-cysteine in a buffered hydromethanolic medium (46).…”

mentioning

confidence: 99%

“…The synthesis of enantio-pyochelin was inspired by the same protocol and started with the condensation of 2-hydroxybenzonitrile with L-cysteine in a buffered hydromethanolic medium (46). The resulting thiazoline, recrystallized from a mixture of ethanol and n-hexane, was then converted into the corresponding Weinreb amide, and the latter was reduced to an aldehyde with lithium aluminum hydride (44,45). The aldehyde was condensed with N-methyl-D-cysteine prepared from D-cysteine according to the procedure of Blondeau et al (47).…”

mentioning

confidence: 99%

Pseudomonas fluorescens CHA0 Produces Enantio-pyochelin, the Optical Antipode of the Pseudomonas aeruginosa Siderophore Pyochelin

Youard

Mislin

Majcherczyk

et al. 2007

Journal of Biological Chemistry

106

123

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The siderophore pyochelin is made by a thiotemplate mechanism from salicylate and two molecules of cysteine. In Pseudomonas aeruginosa, the first cysteine residue is converted to its D-isoform during thiazoline ring formation whereas the second cysteine remains in its L-configuration, thus determining the stereochemistry of the two interconvertible pyochelin diastereoisomers as 4R,2؆R,4؆R (pyochelin I) and 4R,2؆S,4؆R (pyochelin II). Pseudomonas fluorescens CHA0 was found to make a different stereoisomeric mixture, which promoted growth under iron limitation in strain CHA0 and induced the expression of its biosynthetic genes, but was not recognized as a siderophore and signaling molecule by P. aeruginosa. Reciprocally, pyochelin promoted growth and induced pyochelin gene expression in P. aeruginosa, but was not functional in P. fluorescens. The structure of the CHA0 siderophore was determined by mass spectrometry, thin-layer chromatography, NMR, polarimetry, and chiral HPLC as enantio-pyochelin, the optical antipode of the P. aeruginosa siderophore pyochelin. Enantio-pyochelin was chemically synthesized and confirmed to be active in CHA0. Its potential biosynthetic pathway in CHA0 is discussed.

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Iron Chelators and Therapeutic Uses

Bergeron

McManis

Weimar

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

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Iron is an essential cofactor in a variety of biological redox reactions; life without this metal is virtually unknown. Because of its exceptionally poor solubility in the biosphere, bacteria produce relatively low molecular weight, virtually iron(III)‐specific, ligands, siderophores, for the purpose of acquiring this transition metal. On the other hand, higher eukaryotes generate proteins to acquire and store iron. In humans, the process of iron absorption and processing is very tightly controlled. However, the lack of an efficient means of elimination can, under certain conditions, result in iron overload, which can elicit oxidative tissue damage through the Fenton reaction. Accordingly, chelating agents have been tested over the last several decades for the purpose of rendering excess iron excretable. The currently accepted therapy for global iron overload, as occurs after repeated blood transfusions, is a siderophore, desferrioxamine B (DFO), which is administered subcutaneously as its mesylate salt (Desferal). Two synthetic agents, diethylenetriamine pentaacetic acid (DTPA) and 1,2‐dimethyl‐3‐hydroxypyridin‐4‐one (Ferriprox, deferiprone, L1), have been used for the treatment of iron overload as well. Unfortunately, all three of these ligands have drawbacks. The kinetics and lack of oral bioavailability of DFO require that this compound be administered subcutaneously 12 h/day, up to 6 days/week, a regimen with which many patients find it difficult to comply. The lack of chelating specificity of DTPA restricts its use to those who cannot tolerate therapy with DFO; questions remain unanswered regarding the efficacy and toxicity profile of L1. The ongoing efforts to find a worthy successor to DFO include the use of a synthetic agent, N,N ′‐bis(2‐hydroxybenzyl)ethylenediamine‐ N,N ′‐diacetic acid (HBED), which, although it would require subcutaneous administration, is significantly more efficient than DFO. Another avenue is using siderophores (e.g., desferrithiocin, parabactin) as platforms from which to design either orally or parenterally active iron chelators. Because of the necessity of striking a balance between efficacy (i.e., sufficient iron chelation) and toxicity (i.e., excessive iron removal), drug development in the arena of iron chelation therapy presents unique challenges. However, the application of sensible drug design principles predicated on our understanding of iron metabolism, modern synthetic techniques, and the use of appropriate animal models should bring about improved therapeutic agents for the treatment of both global and focal iron overload in the years to come.

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An Improved Stereocontrolled Synthesis of Pyochelin, Siderophore of Pseudomonas aeruginosa and Burkholderia cepacia

Cited by 64 publications

References 25 publications

Stereospecificity of the Siderophore Pyochelin Outer Membrane Transporters in Fluorescent Pseudomonads

Stereospecificity of the Siderophore Pyochelin Outer Membrane Transporters in Fluorescent Pseudomonads

Pseudomonas fluorescens CHA0 Produces Enantio-pyochelin, the Optical Antipode of the Pseudomonas aeruginosa Siderophore Pyochelin

Iron Chelators and Therapeutic Uses

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