title: Identification of a new hexadentate iron chelator capable of restricting the intramacrophagic growth of Mycobacterium avium.
abstract: Iron accumulation has been suggested to contribute to an increase of the susceptibility to mycobacterial infections. In this study we tested the effect of an array of iron chelating ligands of the 3-hydroxy-4-pyridinone family, in the intramacrophagic growth of Mycobacterium avium. We found that bidentate chelators, namely N-alkyl-3-hydroxy-4-pyridinones and N-aryl-3-hydroxy-4-pyridinones, did not affect the growth of M. avium inside mouse macrophages. In the case of the hexadentate chelators, those synthesized using an alkylamine (CP262) or a benzene ring (CP252) to link the three bidentate units, did not have an inhibitory effect on intramacrophagic growth of M. avium while those synthesized from a tripodal structure to anchor the bidentate units were capable of inhibiting the intramacrophagic growth of M. avium. The molecule we designated CP777 had the strongest inhibitory activity. The growth-reducing activity of CP777 was abrogated when this molecule was saturated with iron. These results confirm that iron deprivation, by the use of iron chelating compounds, restricts M. avium growth and that new iron chelators offer an approach to controlling mycobacterial infections.
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Sofia Sousa
authors.initials: SS
authors.lastname: Fernandes
authors.forename: Ana
authors.initials: A
authors.lastname: Nunes
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Gomes
authors.forename: Baltazar
authors.initials: B
authors.lastname: de Castro
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.forename: Maria
authors.initials: M
authors.lastname: Rangel
authors.forename: Rui
authors.initials: R
authors.lastname: Appelberg
authors.forename: Maria Salomé
authors.initials: MS
authors.lastname: Gomes
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009162:Mycobacterium avium / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D002614:Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D007501:Iron