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Molecules 2018, 23(1), 29; https://doi.org/10.3390/molecules23010029

Identification of Inhibitors Targeting Ferredoxin-NADP+ Reductase from the Xanthomonas citri subsp. citri Phytopathogenic Bacteria

1
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, and Institute of Biocomputation and Physics of Complex Systems (BIFI-IQFR and CBsC-CSIC Joint Units), Universidad de Zaragoza, Pedro Cerbuna, 12, 50009 Zaragoza, Spain
2
Departamento de Química Física, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
3
Molecular Biology Division, Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario 2000, Argentina
Present Address: FMC Corporation, Genvej 2, 2790 Hørsholm, Denmark.
*
Author to whom correspondence should be addressed.
Received: 6 November 2017 / Revised: 28 November 2017 / Accepted: 15 December 2017 / Published: 24 December 2017
(This article belongs to the Special Issue Flavoenzymes)
View Full-Text   |   Download PDF [3750 KB, uploaded 24 December 2017]   |  

Abstract

Ferredoxin-NADP(H) reductases (FNRs) deliver NADPH or low potential one-electron donors to redox-based metabolism in plastids and bacteria. Xanthomonas citri subsp. citri (Xcc) is a Gram-negative bacterium responsible for citrus canker disease that affects commercial citrus crops worldwide. The Xcc fpr gene encodes a bacterial type FNR (XccFPR) that contributes to the bacterial response to oxidative stress conditions, usually found during plant colonization. Therefore, XccFPR is relevant for the pathogen survival and its inhibition might represent a strategy to treat citrus canker. Because of mechanistic and structural differences from plastidic FNRs, XccFPR is also a potential antibacterial target. We have optimized an activity-based high-throughput screening (HTS) assay that identifies XccFPR inhibitors. We selected 43 hits from a chemical library and narrowed them down to the four most promising inhibitors. The antimicrobial effect of these compounds was evaluated on Xcc cultures, finding one with antimicrobial properties. Based on the functional groups of this compound and their geometric arrangement, we identified another three XccFPR inhibitors. Inhibition mechanisms and constants were determined for these four XccFPR inhibitors. Their specificity was also evaluated by studying their effect on the plastidic Anabaena PCC 7119 FNR, finding differences that can become interesting tools to discover Xcc antimicrobials. View Full-Text
Keywords: activity-based high-throughput screening; enzyme inhibitors; ferredoxin-NADP(H) reductase; Xanthomonas citri subsp. citri activity-based high-throughput screening; enzyme inhibitors; ferredoxin-NADP(H) reductase; Xanthomonas citri subsp. citri
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Martínez-Júlvez, M.; Goñi, G.; Pérez-Amigot, D.; Laplaza, R.; Ionescu, I.A.; Petrocelli, S.; Tondo, M.L.; Sancho, J.; Orellano, E.G.; Medina, M. Identification of Inhibitors Targeting Ferredoxin-NADP+ Reductase from the Xanthomonas citri subsp. citri Phytopathogenic Bacteria. Molecules 2018, 23, 29.

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