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Deferasirox (ExJade): A Fluorescent Pro-Chelator Active Against Antibiotic Resistant Bacteria

preprint
submitted on 27.03.2020, 15:56 and posted on 30.03.2020, 06:44 by Adam Sedgwick, Kai-Cheng Yan, Daniel N. Mangel, Ying Shang, Axel Steinbrueck, Hai-Hao Han, James T. Brewster, Xi-Le Hu, Dylan W. Snelson, Vincent M. Lynch, He Tian, Xiao-Peng He, Jonathan L. Sessler

Deferasirox, ExJade, an FDA-approved treatment for iron overload disorders has been shown to inhibit the growth of both gram-positive and -negative bacteria through iron (Fe(III)) chelation. Modification of the ExJade framework led to the identification of a new fluorescent platform ExPh and ExBT. Functionalization of the phenol moieties on ExBT with phosphate units afforded a ratiometric fluorescent pro-chelator (ExPhos), which was effective in the inhibition of two clinically relevant antibiotic-resistant bacteria, (MRSA (ATCC 43300) and VRE (ATCC 51299)), and allowed the fluorescent imaging of MRSA. Remarkably, this pro-chelation strategy proved selective towards bacteria with no cytotoxicity observed for ExPhos treated A549 cells (72 h incubation). This work represents a new pro-chelator antibiotic strategy that can be modified with a chosen reactive chemical trigger to provide a diagnostic signal in conjunction with a therapeutic response with a potential of minimal off-target toxicities.

Funding

National Natural Science Foundation of China (Nos 21788102, 91853201, 21722801, 81673489 and 31871414)

Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX03)

International Cooperation Program of Shanghai Science and Technology Committee (No. 17520750100

Fundamental Research Funds for the Central Universities (222201717003)

National Institutes of Health (R01 GM103790 to J.L.S.)

Robert A. Welch Foundation (F-0018)

History

Email Address of Submitting Author

a.c.sedgwick@utexas.edu

Institution

The University of Texas at Austin

Country

United States of America

ORCID For Submitting Author

0000-0002-3132-2913

Declaration of Conflict of Interest

No conflicts of interest

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