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Review
. 2018 Oct 20;11(4):110.
doi: 10.3390/ph11040110.

Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores

Maria Rangel  1 , Tânia Moniz  2 , André M N Silva  3 , Andreia Leite  4
Affiliations
Review

Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores

Maria Rangel et al. Pharmaceuticals (Basel). .

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.

Keywords: 3-hydroxy-4-pyridinone; antibacterial activity; bacteria; fluorescent iron chelator; fluorophore; membrane interactions; rhodamine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Iron chelators in clinical use: desferrioxamine B (DFO), deferasirox (DFX) and deferiprone (DFP).
Figure 2
Figure 2
Schematic representation of the cell envelope of pathogenic mycobacteria (A, adapted from [74]); Structure of mycobacterial siderophores: Mycobactin T produced by M. tuberculosis (MB T); Carboxymycobactin synthetized for M. avium, M. tuberculosis e M. bovis (n = 2–9); Exochelin MS produced for M. smegmatis. (B, adapted from [76,77,78]).
Figure 3
Figure 3
General formula of the 3,4-HPO bidentate chelating unit.
Figure 4
Figure 4
Formulae of 3,4-HPO chelators, CP256 (non-fluorescent ligand), CP851, CP852 (green ligands) and MRH7 (red ligand).
Figure 5
Figure 5
Formulae of fluorescent 3,4-HPO chelators, MRH8, MRB8 and MRB7. The abbreviation and numbering of compounds was assigned according to chelator denticity (MRBi for bidentate and MRHi for hexadentate) and fluorophore (i = 7, 8).
Figure 6
Figure 6
Formulae of fluorescent 3,4-HPO chelators, MRH10 and MRB9. The abbreviation and numbering of compounds was assigned according to chelator denticity (MRBi for bidentate and MRHi for hexadentate) and fluorophore (i = 9–10).
Figure 7
Figure 7
Scheme of a assumed mode of interaction and progress of the rhodamine labelled 3,4-HPO chelators, MRH7 and MRB7 (red) and MRH8 and MRB8 (blue) through the biological membranes, along the permeation process.
Figure 8
Figure 8
Outline of a hypothetical mechanism for the ironing-out effect produced by the rhodamine labelled 3,4-HPO chelators.
Figure 9
Figure 9
Formula of rosamine-derived 3,4-HPO chelator, MRB20.
Figure 10
Figure 10
A graphical representation of past and future fields of application of rhodamine B conjugates.
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