Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

Boradia, Vishant Mahendra; Malhotra, Himanshu; Thakkar, Janak Shrikant; Tillu, Vikas A.; Vuppala, Bhavana; Patil, Pravinkumar; Sheokand, Navdeep; Sharma, Prerna; Chauhan, Anoop Singh; Raje, Manoj; Raje, Chaaya Iyengar

doi:10.1038/ncomms5730

Cited by 92 publications

(85 citation statements)

References 60 publications

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“…When entering bacterial cells by means of siderophores, Fe 3ϩ is reduced to Fe 2ϩ for incorporation into mycobacterial iron-containing proteins, including iron storage proteins like bacterioferritin (1). Other known mycobacterial iron uptake mechanisms include heme uptake (8,9), internalization of holo-transferrin (10), and low-affinity iron uptake through outer membrane porins (11). Guinea pigs and mice infected by M. tuberculosis strains deficient in siderophore synthesis or transport across the cell membrane show a significant reduction in bacterial burden compared to animals infected by wild-type (WT) M. tuberculosis (12,13), demonstrating the need for iron in mycobacterial virulence.…”

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confidence: 99%

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

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Poce

Alfonso

et al. 2015

Antimicrob Agents Chemother

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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.

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confidence: 99%

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

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Poce

Alfonso

et al. 2015

Antimicrob Agents Chemother

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“…Our lab and others have shown that M. tuberculosis replicating in human macrophages can acquire Fe bound to transferrin or lactoferrin and from exogenous sources (13)(14)(15)(16). Fe is an important component of enzymes involved in critical cellular functions such as DNA synthesis (17), general metabolism, and oxidative stress resistance.…”

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Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus

Abdalla

Switzer

Goss

et al. 2015

Antimicrob Agents Chemother

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The rapidly growing nontuberculous mycobacterial species Mycobacterium abscessus has recently emerged as an important pathogen in patients with cystic fibrosis (CF). Treatment options are limited because of the organism's innate resistance to standard antituberculous antibiotics, as well as other currently available antibiotics. New antibiotic approaches to the treatment of M. abscessus are urgently needed. The goal of the present study was to assess the growth-inhibitory activity of different Ga compounds against an American Type Culture Collection (ATCC) strain and clinical isolates of M. abscessus obtained from CF and other patients. In our results, using Ga(NO 3 ) 3 and all of the other Ga compounds tested inhibited the growth of ATCC 19977 and clinical isolates of M. abscessus. Inhibition was mediated by disrupting iron uptake, as the addition of exogenous iron (Fe) restored basal growth. There were modest differences in inhibition among the isolates for the same Ga chelates, and for most Ga chelates there was only a slight difference in potency from Ga(NO 3 ) 3 . In contrast, Ga-protoporphyrin completely and significantly inhibited the ATCC strain and clinical isolates of M. abscessus at much lower concentrations than Ga(NO 3 ) 3 . In in vitro broth culture, Ga-protoporphyrin was more potent than Ga(NO 3 ) 3 . When M. abscessus growth inside the human macrophage THP-1 cell line was assessed, Ga-protoporphyrin was >20 times more active than Ga(NO 3 ) 3 . The present work suggests that Ga exhibits potent growth-inhibitory capacity against the ATCC strain, as well as against antibiotic-resistant clinical isolates of M. abscessus, including the highly antibiotic-resistant strain MC2638. Ga-based therapy offers the potential for further development as a novel therapy against M. abscessus.

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“…Boradia et al [40] reported the over-expression of GAPDH, correlated with a corresponding increase in transferrin binding and iron uptake in mycobacteria. Spot 11 is probable CoAtransferase alpha subunit (Rv3551).…”

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confidence: 98%