Fluorescent 3-hydroxy-4-pyridinone hexadentate iron chelators: intracellular distribution and the relevance to antimycobacterial properties |
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Authors: | Ana Nunes Maria Podinovskaia Andreia Leite Paula Gameiro Tao Zhou Yongmin Ma Xiaole Kong Ulrich E Schaible Robert C Hider Maria Rangel |
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Institution: | 1. REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, 4069-007, Porto, Portugal 2. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK 3. Division of Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, London, SE1 9NH, UK 4. College of Food and Biotechnology, Zhejiang Gongshang University, Hangzhou, 310035, People’s Republic of China 5. Department of Molecular Infection Biology, Research Center Borstel, 23845, Borstel, Germany 6. REQUIMTE, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4099-003, Porto, Portugal
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Abstract: | Abstract We report the synthesis and characterization of a fluorescent iron chelator (4), shown to be effective in inhibiting the growth of Mycobacterium avium in macrophages, together with the synthesis and characterization of two unsuccessful analogues selected to facilitate identification
of the molecular properties responsible for the antimicrobial activity. Partition of the chelators in liposomes was investigated
and the compounds were assessed with respect to uptake by macrophages, responsiveness to iron overload/iron deprivation and
intracellular distribution by flow cytometry and confocal microscopy. The synthesis of the hexadentate chelators is based
on a tetrahedral structure to which three bidentate 3-hydroxy-4-pyridinone chelating units are linked via amide bonds. The
structure is synthetically versatile, allowing further addition of functional groups such as fluorophores. Here, we analyse
the non-functionalized hexadentate unit (3) and the corresponding rhodamine B (4) and fluorescein (5) labelled chelators. The iron(III) stability constant was determined for 3 and the values log β = 34.4 and pFe3+ = 29.8 indicate an affinity for iron of the same order of magnitude as that of mycobacteria siderophores. Fluorescence properties
in the presence of liposomes show that 4 strongly interacts with the lipid phase, whereas 5 does not. Such different behaviour may explain their distinct intracellular localization as revealed by confocal microscopy.
The flow cytometry and confocal microscopy studies indicate that 4 is readily engulfed by macrophages and targeted to cytosol and vesicles of the endolysosomal continuum, whereas 5 is differentially distributed and only partially colocalizes with 4 after prolonged incubation. Differential distribution of the compounds is likely to account for their different efficacy
against mycobacteria. |
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