[PMID]: | 25645825 |
[Au] Autor: | Dragset MS; Poce G; Alfonso S; Padilla-Benavides T; Ioerger TR; Kaneko T; Sacchettini JC; Biava M; Parish T; Argüello JM; Steigedal M; Rubin EJ |
[Ad] Endereço: | Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA Department of Biotechnology, Norwegian University of Science and Technology, Trondheim, Norway Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medic |
[Ti] Título: | A novel antimycobacterial compound acts as an intracellular iron chelator. |
[So] Source: | Antimicrob Agents Chemother;59(4):2256-64, 2015 Apr. |
[Is] ISSN: | 1098-6596 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound. |
[Mh] Termos MeSH primário: |
Antibacterianos/farmacologia Quelantes de Ferro/farmacologia Mycobacterium smegmatis/efeitos dos fármacos Pirazóis/farmacologia Pirimidinonas/farmacologia
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[Mh] Termos MeSH secundário: |
Farmacorresistência Bacteriana/efeitos dos fármacos Farmacorresistência Bacteriana/genética Ferrozina/metabolismo Ferro/metabolismo Testes de Sensibilidade Microbiana Mycobacterium smegmatis/genética Oxazóis/metabolismo Pirazóis/síntese química Pirimidinonas/síntese química RNA Bacteriano/metabolismo Sideróforos/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (3-(4-chlorophenyl)-5-(cyclohexylmethyl)pyrazolo(1,5-a)pyrimidin-7(4H)-one); 0 (Anti-Bacterial Agents); 0 (Iron Chelating Agents); 0 (Oxazoles); 0 (Pyrazoles); 0 (Pyrimidinones); 0 (RNA, Bacterial); 0 (Siderophores); 0 (mycobactins); 28048-33-1 (Ferrozine); E1UOL152H7 (Iron) |
[Em] Mês de entrada: | 1512 |
[Cu] Atualização por classe: | 161202 |
[Lr] Data última revisão:
| 161202 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 150204 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1128/AAC.05114-14 |
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