title: A novel antimycobacterial compound acts as an intracellular iron chelator.
abstract: 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.
authors: 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 Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors: Marte S
authors: MS
authors: Dragset
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy.
authors: Giovanna
authors: G
authors: Poce
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy.
authors: Salvatore
authors: S
authors: Alfonso
authors: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, Massachusetts, USA.
authors: Teresita
authors: T
authors: Padilla-Benavides
authors: Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, USA.
authors: Thomas R
authors: TR
authors: Ioerger
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: Takushi
authors: T
authors: Kaneko
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors: James C
authors: JC
authors: Sacchettini
authors: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy.
authors: Mariangela
authors: M
authors: Biava
authors: Infectious Disease Research Institute, Seattle, Washington, USA.
authors: Tanya
authors: T
authors: Parish
authors: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, Massachusetts, USA.
authors: José M
authors: JM
authors: Argüello
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway Central Norway Regional Health Authority, Stjørdal, Norway erubin@hsph.harvard.edu magnus.steigedal@ntnu.no.
authors: Magnus
authors: M
authors: Steigedal
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA erubin@hsph.harvard.edu magnus.steigedal@ntnu.no.
authors: Eric J
authors: EJ
authors: Rubin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D005297:Ferrozine / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000235:genetics; D010080:Oxazoles / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000378:metabolism; D017262:Siderophores / Q000378:metabolism
chemical_list: C000603505:3-(4-chlorophenyl)-5-(cyclohexylmethyl)pyrazolo(1,5-a)pyrimidin-7(4H)-one; D000900:Anti-Bacterial Agents; D007502:Iron Chelating Agents; D010080:Oxazoles; D011720:Pyrazoles; D011744:Pyrimidinones; D012329:RNA, Bacterial; D017262:Siderophores; C018608:mycobactins; D005297:Ferrozine; D007501:Iron
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