Rhodamine labeling of 3-hydroxy-4-pyridinone iron chelators is an important contribution to target Mycobacterium avium infection

• Published in: Journal of inorganic biochemistry 2013-04, Vol.121, p.156-166
• Main Authors: Moniz, Tânia, Nunes, Ana, Silva, Ana M.G., Queirós, Carla, Ivanova, Galya, Gomes, M.S., Rangel, Maria
• Format: Article
• Language: English
• Subjects: 3-Hydroxy-4-pyridinones; Animals; Colony Count, Microbial; Drug Design; Fluorescent chelators; Fluorescent Dyes - chemistry; Fluorescent Dyes - pharmacology; Infection; Iron; Iron - metabolism; Iron Chelating Agents - chemical synthesis; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacology; Ligands; Macrophages - drug effects; Macrophages - microbiology; Mice; Mice, Knockout; Mycobacterium avium; Mycobacterium avium - drug effects; Mycobacterium avium - growth & development; Mycobacterium avium - metabolism; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Rhodamine; Rhodamines - chemistry; Rhodamines - pharmacology; Structure-Activity Relationship
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2013.01.002

We have recently demonstrated that tripodal hexadentate chelators, based on 3-hydroxy-4-pyridinone units, can limit the access of iron to bacteria and have a significant inhibitory effect in the intramacrophagic growth of Mycobacterium avium. The results showed that the chelation of iron is a determinant although not sufficient property for antimicrobial activity. The rhodamine B isothiocyanate labelled chelator (MRH7) exhibited the strongest inhibitory activity and was identified as a lead compound since a dose response effect was observed. Significant inhibition of M. avium growth was achieved at a concentration as low as 1μM. To identify key molecular features essential for the biological activity we designed parent hexadentate and bidentate chelators, in which different structural groups are introduced in the molecular framework. Herein, we report the work concerning three novel fluorescent chelators: a hexadentate ligand labelled with 5(6)-carboxytetramethylrhodamine (MRH8) and two 3-hydroxy-4-pyridinone fluorescent bidentate ligands labelled with rhodamine B isothiocyanate (MRB7) and 5(6)-carboxytetramethylrhodamine (MRB8). The results show that all fluorescent chelators are capable of restricting the intramacrophagic growth of M. avium and that the inhibitory effect is dependent on the fluorophore. In fact, for compounds bearing the same fluorophore the results obtained with the hexadentate or bidentate chelator (MRH7/MRB7 or MRH8/MRB8) are identical as long as the appropriate stoichiometric amount of chelator is used. The inhibitory effect of the rhodamine B isothiocyanate labelled compounds (MRH7 and MRB7) is significantly greater than that observed for the other two chelators, thus pointing out the significance of the rhodamine B isothiocyanate molecular fragment. The conjugation of rhodamine fluorophores to 3-hydroxy-4-pyridinone chelating units is determinant to target Mycobacterium avium infection through an ironing-out effect. [Display omitted] ► Synthesis and characterization of three novel 3-hydroxy-4-pyridinone fluorescent chelators. ► All fluorescent chelators are capable of restricting the intramacrophagic growth of M. avium. ► The results point out the significance of the rhodamine B isothiocyanate molecular fragment to target mycobacterial infection.