Identification of a new hexadentate iron chelator capable of restricting the intramacrophagic growth of Mycobacterium avium.
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.
Fernandes
Sofia Sousa
SS
IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Nunes
Ana
A
Gomes
Ana Rita
AR
de Castro
Baltazar
B
Hider
Robert C
RC
Rangel
Maria
M
Appelberg
Rui
R
Gomes
Maria Salomé
MS
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*
D000995:Antitubercular Agents; D002614:Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D007501:Iron