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

Abstract

<p>Deferasirox,<b> ExJade</b>, 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 <b>ExJade</b> framework led to the identification of a new fluorescent platform <b>ExPh </b>and <b>ExBT</b>. Functionalization of the phenol moieties on <b>ExBT</b> with phosphate units afforded a ratiometric fluorescent pro-chelator (<b>ExPhos</b>), 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. <a>Remarkably, this pro-chelation strategy proved selective towards bacteria with no cytotoxicity observed for <b>ExPhos</b> treated A549 cells (72 h incubation). This work represents a new pro-chelator antibiotic strategy that </a><a>can be modified with a chosen reactive chemical trigger to provide a diagnostic signal in conjunction with a therapeutic response</a> with a potential of minimal off-target toxicities.</p>

Exploring Titanium(IV) Complexes as Potential Antimicrobial Compounds

“…The Fe binding property of Ti(Deferasirox) 2 may play a significant role in its inhibition of MRSA by disrupting Fe bioavailability. This possibility is supported by the recent preprint work by Sessler et al, which demonstrated that a prochelator form of deferasirox could inhibit MRSA up to 70% at 15 µM [4,69]. Ti(Deferasirox) 2 can be viewed as a prochelator with it displaying high extracellular stability and intracellular Fe-induced transmetalation [36].…”

“…Given the central role that essential metals can play in microbial growth and the distinctive chemistry that can be facilitated by metals coupled with the varied structures and properties that they can adopt from ligand complexation, metal-centered antimicrobial strategies are an exciting new research avenue. One approach is developing compounds that can uniquely perturb the essential metal homeostasis within pathogenic microbes and possibly even attenuate their bioavailability [ 1 , 2 , 3 , 4 ]. Another approach is assessing the therapeutic potential of metals in ion or complex form.…”

Titania supported dioxidotungsten(vi) complex as bio-mimic for the type II copper-containing oxidase enzyme phenoxazinone synthase

“…9 On the other hand, the tridentate chelator deferasirox (DFX or ICL670, I of Scheme 1), initially reported in 1999, 10 was the first oral medication for iron overload to be accepted by the Food and Drug Administrations (FDA) in 2005, and later by the European Medicines Agency in 2006. 11,12 Recently, DFX combined with deferiprone has been reported to eliminate thallium from rats’ organs. 13 Recent investigations have shown that DFX can be used as an effective chemotherapeutic, 14,15 antifungal, 16 and antimicrobial agent.…”