<i>De novo</i> synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by <i>Pseudomonas aeruginosa</i>

Zhang, Jian; Zhao, Tianhu; Yang, Ruining; Siridechakorn, Ittipon; Wang, Sanshan; Guo, Qianqian; Bai, Yanjie; Shen, Hong C.; Lei, Xiaoguang

doi:10.1039/c9sc01405e

Cited by 26 publications

(30 citation statements)

References 46 publications

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“…By the time this article was prepared, Zhang et al published the asymmetric synthesis of 4a and 4b , along with the attribution of the ( S,S,S ) configuration (the one of 4b ) to the natural product. This synthesis relies, as the one the same authors proposed for compound 3 , on the conversion of the amino groups in sulfonamides which are engaged, in turn, in an asymmetric Tsuji–Trost and a Fukuyama–Mitsunobu reactions.…”

Section: Resultsmentioning

confidence: 99%

“…In this paper, we present a new synthesis of the two epimers of pseudopaline ( 4 ). This approach represents an alternative strategy for the synthesis of pseudopaline (and, in general, of opine metallophores) to the one exploited by Zhang et al, thanks to a reduced number of steps (5, starting from commercially available 7 , vs. 8), comparable overall yields (24 % vs. 22 %), and greener conditions avoiding the use of transition metals, toxic oxidizing reagents, and of non‐atom efficient reactions (i.e. Fukuyama–Mitsunobu).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Two Epimers of Pseudopaline

et al. 2020

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Opines are a known group of compounds characterized by an elevated polarity. Recently, two new members of this class, staphylopine and pseudopaline, have been identified in Staphylococcus aureus and Pseudomonas aeruginosa, respectively. These molecules are metal chelators that contribute to the growth of bacteria in particularly metal‐poor environment. Different evidences suggest that these molecules might have an important role in the development of pulmonary infections in humans. Considering the impact of P. aeruginosa infections in cystic fibrosis patients (prevalence up to 70 %), pseudopaline has risen interest as potential source of new therapeutic intervention. We present herein a straightforward synthetic approach for the synthesis of the two epimers of pseudopaline. Starting from a chiral building block, we attribute the absolute configuration to the two obtained diasteroisomers.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis of Two Epimers of Pseudopaline

et al. 2020

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“…We hypothesized that SaODH and PaODH would catalyze reversible reactions and that both enzymes would exclusively form the (R)-product diastereomer, consistent with structurally homologous opine dehydrogenases (18 -20). To test this hypothesis, (R)-and (S)-pseudopaline and (R)-and (S)-staphylopine were synthesized as previously described (10,21). SaODH or PaODH were combined with NADP ϩ and then mixed with varied concentrations of (R)-or (S)-staphylopine (SaODH) or (R)-or (S)-pseudopaline (PaODH) ( Fig.…”

Section: Saodh and Paodh Catalyze Reversible Reactionsmentioning

confidence: 99%

“…Interestingly, it was recently shown that when 100 M (S)pseudopaline is added to WT P. aeruginosa PAO1 grown on Vogel-Bonner minimal media with 50 M of added EDTA the intracellular concentrations of Zn(II), Fe(II), Co(II), and Ni(II) are increased (10). 100 M (R)-pseudopaline did not increase metal uptake compared with WT P. aeruginosa PAO1 grown in the absence of any added metallophore.…”

Section: Opine Dehydrogenase Stereospecificity and Mechanismmentioning

confidence: 99%

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Staphylopine and pseudopaline dehydrogenase from bacterial pathogens catalyze reversible reactions and produce stereospecific metallophores

McFarlane

Zhang

Wang

et al. 2019

Journal of Biological Chemistry

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Edited by Ruma Banerjee Pseudopaline and staphylopine are opine metallophores biosynthesized by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The final step in opine metallophore biosynthesis is the condensation of the product of a nicotianamine (NA) synthase reaction (i.e. L-HisNA for pseudopaline and D-HisNA for staphylopine) with an ␣-keto acid (␣-ketoglutarate for pseudopaline and pyruvate for staphylopine), which is performed by an opine dehydrogenase. We hypothesized that the opine dehydrogenase reaction would be reversible only for the opine metallophore product with (R)-stereochemistry at carbon C2 of the ␣-keto acid (prochiral prior to catalysis). A kinetic analysis using stopped-flow spectrometry with (R)-or (S)-staphylopine and kinetic and structural analysis with (R)-and (S)-pseudopaline confirmed catalysis in the reverse direction for only (R)-staphylopine and (R)-pseudopaline, verifying the stereochemistry of these two opine metallophores. Structural analysis at 1.57-1.85 Å resolution captured the hydrolysis of (R)-pseudopaline and allowed identification of a binding pocket for the L-histidine moiety of pseudopaline formed through a repositioning of Phe-340 and Tyr-289 during the catalytic cycle. Transient-state kinetic analysis revealed an ordered release of NADP ؉ followed by staphylopine, with staphylopine release being the rate-limiting step in catalysis. Knowledge of the stereochemistry for opine metallophores has implications for future studies involving kinetic analysis, as well as opine metallophore transport, metal coordination, and the generation of chiral amines for pharmaceutical development.

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Dipicolylamine‐Zn Induced Targeting and Photo‐Eliminating of Pseudomonas aeruginosa and Drug‐Resistance Gram‐Positive Bacteria

Wang,

Cai,

Ning

et al. 2023

Adv Healthcare Materials

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The emergence of drug‐resistant bacteria, particularly resistant strains of Gram‐negative bacteria, such as Pseudomonas aeruginosa, poses significant threat to public health. Although antibacterial photodynamic therapy (APDT) is a promising strategy for combating drug‐resistant bacteria, actively targeted photosensitizers (PSs) remain unknown. In this study, a PS based on dipicolylamine (DPA), known as WZK‐DPA‐Zn, was designed for the selective identification of P. aeruginosa and drug‐resistant Gram‐positive bacteria. WZK‐DPA‐Zn exploited the synergistic effects of DPA‐Zn2+ coordination and cellular uptake, which could effectively anchor P. aeruginosa within a brief period (10 min) without interference from other Gram‐negative bacteria. Simultaneously, the cationic nature of WZK‐DPA‐Zn enhanced its interaction with Gram‐positive bacteria via electrostatic forces. Compared to traditional clinical antibiotics, WZK‐DPA‐Zn showed exceptional antibacterial activity without inducing drug resistance. This effectiveness was achieved using the APDT strategy when irradiated with white light or sunlight. The combination of WZK‐DPA‐Zn with Pluronic‐based thermosensitive hydrogel dressings (WZK‐DPA‐Zn@Gel) effectively eliminated mixed bacterial infections and accelerated wound healing, thereby achieving a synergistic effect where 1+1>2″. In summary, this study proposes a precise strategy employing DPA‐Zn as the targeting moiety of a PS, facilitating the rapid elimination of P. aeruginosa and drug‐resistant Gram‐positive bacteria using APDT.This article is protected by copyright. All rights reserved

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De novo synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by Pseudomonas aeruginosa

Abstract: The first total synthesis and isolation of pseudopaline was reported, which allows determination and confirmation of the absolute configuration of the natural product.

Cited by 26 publications

References 46 publications

Synthesis of Two Epimers of Pseudopaline

Synthesis of Two Epimers of Pseudopaline

Staphylopine and pseudopaline dehydrogenase from bacterial pathogens catalyze reversible reactions and produce stereospecific metallophores

Dipicolylamine‐Zn Induced Targeting and Photo‐Eliminating of Pseudomonas aeruginosa and Drug‐Resistance Gram‐Positive Bacteria

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