Multifunctional iron chelators to combat antibiotic resistance and enable bacterial imaging

Deferasirox derivatives, such as ExPh and ExBT, are designed to chelate iron and inhibit antibiotic-resistant bacteria like MRSA and VRE. They exhibit unique fluorescent properties for bacterial imaging, offering both therapeutic and diagnostic capabilities.

Background

Antibiotic resistance is a growing public health concern, driven by the rapid evolution of bacteria and the widespread misuse of antibiotics. This has led to the emergence of “superbugs,” bacteria that are resistant to multiple antibiotics, posing a significant threat to global health. Traditional antibiotics often fail to combat these resistant strains, necessitating the development of novel therapeutic strategies.

One promising approach involves the use of iron chelators, which can disrupt bacterial iron acquisition—a critical process for bacterial growth and biofilm formation. However, existing iron chelators, such as deferasirox, while effective in chelating iron, are associated with significant toxicity and lack specificity, leading to potential off-target effects.

This has spurred interest in developing advanced chelators that can be activated in response to specific bacterial enzymes or environmental conditions, thereby minimizing systemic toxicity and enhancing therapeutic efficacy. Additionally, the integration of diagnostic capabilities into these therapeutic agents could provide a dual function of treatment and real-time monitoring of bacterial infections, offering a comprehensive solution to the challenge of antibiotic resistance.

Technology description

The technology involves the creation of novel derivatives of the iron chelator deferasirox (ExJade), traditionally used for treating iron overload disorders. These new derivatives, such as ExPh and ExBT, possess unique photophysical properties, including aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT), which make them fluorescent in aqueous environments.

Designed as pro-chelators, these compounds remain inactive until activated by specific stimuli, such as alkaline phosphatase, an enzyme expressed by certain bacteria. Upon activation, they chelate iron (Fe(III)), inhibiting the growth of antibiotic-resistant bacteria like MRSA and VRE. Additionally, their fluorescence properties enable optical imaging of bacterial infections, offering both therapeutic and diagnostic capabilities.

This technology is differentiated by its dual functionality, combining therapeutic action with diagnostic imaging. The derivatives leverage the unique properties of deferasirox to target bacterial infections selectively, reducing the risk of systemic toxicity associated with off-target metal chelation. The inherent fluorescence of these compounds eliminates the need for additional fluorophores, simplifying the design and reducing synthetic complexity.

By exploiting bacterial-specific enzymes for activation, the technology provides a targeted approach to combating antibiotic resistance, addressing a critical need in the face of rising superbug threats. This innovative strategy not only enhances the efficacy of bacterial inhibition but also facilitates real-time monitoring of infection sites, offering a comprehensive solution in the fight against resistant bacterial strains.

Benefits

Development of new derivatives of deferasirox with unique photophysical properties
Versatility in modifying the deferasirox scaffold for various applications
Inhibits growth of antibiotic-resistant bacteria like MRSA and VRE
Enables optical imaging of bacterial infections via fluorescent properties
Potential for targeted bacterial inhibition and imaging through pro-chelator activation
Novel approach to combating antibiotic resistance
Reduced systemic toxicity due to pro-chelator design
Possible applications in both therapeutic and diagnostic fields
Enhanced efficacy and safety profile compared to traditional antibiotics
Potential for use in imaging and treating biofilms