Abstract
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure of mycobacterial siderophores and considering that new chelators must be able to compete for Fe(III), we selected ligands of the 3-hydroxy-4-pyridinone class to achieve our purpose. After choosing the type of chelating unit it was also our objective to design chelators that could be monitored inside the cell and for that reason we designed chelators that could be functionalized with fluorophores. We didn’t realize at the time that the incorporation a fluorophore, to allow spectroscopic detection, would be so relevant for the antimycobacterial effect or to determine the affinity of the chelators towards biological membranes. From a biophysical perspective, this is a fascinating illustration of the fact that functionalization of a molecule with a particular label may lead to a change in its membrane permeation properties and result in a dramatic change in biological activity. For that reason we believe it is interesting to give a critical account of our entire work in this area and justify the statement “to label means to change”. New perspectives regarding combined therapeutic approaches and the use of rhodamine B conjugates to target closely related problems such as bacterial resistance and biofilm production are also discussed.
Highlights
Numerous transition metal ions have proved to be essential for life, though it is well known that transition metals can be toxic
DFO has been used to inhibit Mycobacterium aurum growth [96] and another study suggested that DFO in combination with silybin, an iron-chelating agent from plants, was able to reduce the extracellular growth of M. tuberculosis
Namely spiro pyridopyrrolizines, pyrrolidines [99] and 4H-pyrano[3,2-c]pyridine derivatives [100], have been tested and the results have shown that the compounds are effective to inhibit the in vitro growth of M. tuberculosis
Summary
Numerous transition metal ions have proved to be essential for life, though it is well known that transition metals can be toxic. The suitability of Fe arises from its unique physico-chemical properties to act in electron transfer, namely the possibility of existing in various oxidation states and the extreme variability of its redox potentials, which can be fine-tuned upon chelation [11,12]. This redox activity can be pernicious if the element exists in chemical forms with redox potentials that allow their participation in the generation of reactive oxygen species (ROS) [13]. Natural and synthetic Fe chelators have first been used to treat iron overload diseases and at present three types of chelators (desferrioxamine (DFO), desferasirox (DFX) and deferiprone (DFP)) (Figure 1) are used in clinical practice [18,20,21,22]. From the chemical point of view the structure of new antimicrobial agents should differ from that of natural siderophores in order to prevent the recognition and uptake of the iron-chelate by the pathogens
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
