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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.

SUBMITTER: Dragset MS

PROVIDER: S-EPMC4356758 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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A novel antimycobacterial compound acts as an intracellular iron chelator.

Dragset Marte S MS Poce Giovanna G Alfonso Salvatore S Padilla-Benavides Teresita T Ioerger Thomas R TR Kaneko Takushi T Sacchettini James C JC Biava Mariangela M Parish Tanya T Argüello José M JM Steigedal Magnus M Rubin Eric J EJ

Antimicrobial agents and chemotherapy 20150202 4

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, ...[more]

PMID: 25645825

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Project description:Iron is an essential micronutrient due to its involvement in many cellular processes including DNA replication and OXPHOS. Tumors overexpress iron metabolism linked proteins which allow for iron accumulation driving high levels of proliferation. Our group has designed novel iron chelator SK4 which targets cancer's "iron addiction." SK4 comprises of two key moieties: an iron chelation moiety responsible for cytotoxicity and an amino acid moiety which allows entry through amino acid transporter LAT1. We selected LAT1 as a route of entry as it is commonly overexpressed in malignant tumors. SK4 has previously demonstrated promising results in an in vitro model for melanoma. We hypothesized SK4 would be effective against a range of tumor types. We have screened a panel of tumor-derived cell lines from different origins including breast, prostate, ovarian and cervical cancer for SK4 sensitivity and we have found a range of differential sensitivities varying from 111.3 to >500 μM. We validated the iron chelation moiety as responsible for inducing cytotoxicity through control compounds; each lacking a key moiety. Following the screen, we conducted a series of assays to elucidate the mechanism of action behind SK4 cytotoxicity. SK4 was shown to induce apoptosis in triple negative breast cancer cell line MDA MB 231 but not ovarian cancer cell line SKOV3 suggesting SK4 may induce different modes of cell death in each cell line. As MDA MB 231 cells harbor a mutation in p53, we conclude SK4 is capable of inducing apoptosis in a p53-independent manner. SK4 upregulated NDRG1 expression in MDA MB 231 and SKOV3 cells. Interestingly, knockdown of NDRG1 antagonized SK4 in MDA MB 231 cells but not SKOV3 cells suggesting SK4's mechanism of action may be mediated through NDRG1 in MDA MB 231 cells. In conclusion, we have shown tagging iron chelators with an amino acid moiety to allow entry through the LAT1 transporter represents a double pronged approach to cancer therapy, targeting "iron addiction" and amino acid metabolism dysregulation.

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A novel antimycobacterial compound acts as an intracellular iron chelator.

Publications

A novel antimycobacterial compound acts as an intracellular iron chelator.

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