The influence of functional groups on the permeation and distribution of antimycobacterial rhodamine chelators

We formerly hypothesized a mechanism whereby the antimycobacterial efficiency of a set of rhodamine labelled iron chelators is improved via the rhodamine fluorophore which enhances the chelators' permeation properties through membranes. To validate our hypothesis in a cellular context and to understand the influence of the structure of the fluorophore on the chelator's uptake and distribution within macrophages we now report comparative confocal microscopy studies performed with a set of rhodamine labelled chelators. We identify the functional groups of the chelator's framework that favor uptake by macrophages and conclude that the antimycobacterial effect is strongly related with the capacity of the chelator to distribute within the host cell and its compartments, a property that is closely related with the chelators' ability to interact with membranes. The quantification of the chelators' interaction with membranes was assessed through measurement of the corresponding partition constants in liposomes. The overall results support that the compounds which are preferentially taken up are the most efficient antimycobacterial chelators and for that reason we infer that the biological activity is modulated by the structural features of the fluorophore. The structural features of rhodamine-labelled 3-hydroxy-4-pyridinones chelators determine chelators' permeation through biological membranes and their cellular uptake by macrophages. Accordingly, these chelators have a superior ability to reach the infection target, an important point that improves their efficacy as antimycobacterial agents for controlling intramacrophagic growth of Mycobacterium avium. [Display omitted] •Rhodamine labelling of pyridinones improves chelators' affinity to lipid phases.•N-ethyl groups and a thiourea linkage favor chelators' permeation across membranes.•Chelators' permeation properties are decisive for antibacterial effect.