The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses

Horwitz, Lawrence D.; Horwitz, Marcus A.

doi:10.1089/ars.2013.5789

Cited by 12 publications

(12 citation statements)

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“…Accordingly, Fe-cMBT might also enter the bacterial cytosol by traversing the inner membrane without facilitation by (a) transporter(s). Along the same line, some data support the notion that the carboxylate moiety of cMBT might be esterified (Gobin et al, 1995;Wong, Gobin, Horwitz, & Gibson, 1996;Hodges, Weinberger, Stephens, Horwitz, & Horwitz, 2006;Horwitz et al, 2014), thus also increasing the amphipathic features and membrane permeability of the siderophore.…”

Section: Marinum δMbtb and δMbtb-δirtab Hyg Are Impaired For Gromentioning

confidence: 59%

“…The accumulation of mycobactins must be controlled by the bacteria, as these siderophores become toxic in high doses (Jones et al, 2014). In addition to IrtAB, other transporters and/or reductases might be involved in the transportation of mycobactins across the inner membrane into the cytosol and/or Fe 3+ reduction (Brown & Ratledge, 1975;Horwitz & Horwitz, 2014;Ratledge, 1971).…”

Section: Marinum δMbtb and δMbtb-δirtab Hyg Are Impaired For Gromentioning

confidence: 99%

“…Pathogenic mycobacteria, such as M. tuberculosis, produce two siderophore variants, which are produced by nonribosomal peptide synthetases and polyketide synthases: the hydrophobic mycobactin (MBT; Snow, 1965) and the more water-soluble carboxymycobactin (cMBT; Gobin et al, 1995), together also referred to as mycobactins (Chao, Sieminski, Owens, & Goulding, 2019;Sritharan, 2016;Wilson, Bogdan, Miyazawa, Hashimoto, & Tsuji, 2016). Environmental, non-pathogenic mycobacteria, such as Mycobacterium smegmatis, additionally produce a distinct class of siderophores called exochelins (Horwitz & Horwitz, 2014;Sharman, Williams, Ewing, & Ratledge, 1995).…”

mentioning

confidence: 99%

“…IrtA contains a highly conserved, N-terminal siderophore-interacting domain, which is likely involved in the reduction of mycobactin-bound ferric iron at the cytoplasmc side of the inner membrane and the consequent release of ferrous iron (Ryndak, Wang, Smith, & Rodriguez, 2010). Compared with MBT, cMBT has a more amphipathic character, and Fe-cMBT might traverse the membrane-at least to some extent-without support from transporters (Horwitz & Horwitz, 2014).…”

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confidence: 99%

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Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes

Knobloch

Koliwer‐Brandl

Arnold

et al. 2020

Cellular Microbiology

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Mycobacterium marinum is a model organism for pathogenic Mycobacterium species, including Mycobacterium tuberculosis, the causative agent of tuberculosis. These pathogens enter phagocytes and replicate within the Mycobacterium‐containing vacuole, possibly followed by vacuole exit and growth in the host cell cytosol. Mycobacteria release siderophores called mycobactins to scavenge iron, an essential yet poorly soluble and available micronutrient. To investigate the role of M. marinum mycobactins, we purified by organic solvent extraction and identified by mass spectrometry the lipid‐bound mycobactin (MBT) and the water‐soluble variant carboxymycobactin (cMBT). Moreover, we generated by specialised phage transduction a defined M. marinum ΔmbtB deletion mutant predicted to be defective for mycobactin production. The M. marinum ΔmbtB mutant strain showed a severe growth defect in broth and phagocytes, which was partially complemented by supplying the mbtB gene on a plasmid. Furthermore, purified Fe‐MBT or Fe‐cMBT improved the growth of wild type as well as ΔmbtB mutant bacteria on minimal plates, but only Fe‐cMBT promoted the growth of wild‐type M. marinum during phagocyte infection. Finally, the intracellular growth of M. marinum ΔmbtB in Acanthamoeba castellanii amoebae was restored by coinfection with wild‐type bacteria. Our study identifies and characterises the M. marinum MBT and cMBT siderophores and reveals the requirement of mycobactins for extra‐ and intracellular growth of the pathogen.

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Section: Marinum δMbtb and δMbtb-δirtab Hyg Are Impaired For Gromentioning

confidence: 59%

Section: Marinum δMbtb and δMbtb-δirtab Hyg Are Impaired For Gromentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes

Knobloch

Koliwer‐Brandl

Arnold

et al. 2020

Cellular Microbiology

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“…Iron is also involved in bacterial virulence and pathogenesis (18,19). Therefore, Fe metabolism and the Fe uptake pathway are potential therapeutic targets for new antibiotics (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

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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Developing Ligands to Target Transition Metals in Cancer

Utterback

Tomat

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Transition metals are essential for the function for numerous metalloproteins and cofactors in living systems. Their acquisition, transport, and storage are tightly regulated and the homeostasis of redox‐active cations such as iron and copper is especially critical to prevent the damaging effects of oxidative stress. Indeed the dyshomeostasis of metals has been observed in the pathophysiology of several diseases, and multiple metal‐binding compounds are currently under investigation as therapeutic candidates. Herein, we focus on the altered metal metabolisms of malignant cells and on metal‐binding strategies for the design of cancer chemotherapeutics. Iron, copper, and zinc chelators with a variety of binding motifs have been studied for their antiproliferative effects in malignant cells, and several compounds have reached clinical trials. Recent pro‐chelation approaches, in which the chelator is activated under specific conditions, are poised to increase therapeutic indexes and avoid unwanted side effects. As additional information emerges on the roles of metals in cancer biology, the design of metal‐binding drug candidates is evolving to improve their selectivity and efficacy and to consider their effects on the immune cells present in the tumor microenvironment. In addition, extensive studies to develop inhibitors of metalloenzymes relevant to cancer growth have led to several new anticancer therapeutics that coordinate the zinc centers in the active site of the enzymes. As illustrated by the examples collected herein, approaches that target either labile or protein‐bound transition metals have significant potential to produce new therapeutic options for cancer treatment.

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The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses

Cited by 12 publications

References 58 publications

Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes

Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes

Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus

Developing Ligands to Target Transition Metals in Cancer

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