Breaking a pathogen's iron will: Inhibiting siderophore production as an antimicrobial strategy

Lamb, Audrey L.

doi:10.1016/j.bbapap.2015.05.001

Cited by 88 publications

(88 citation statements)

References 116 publications

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“…This report demonstrates the enormous potential of targeting siderophore biosynthesis pathways using these natural baulamycins, which can be further modified to enhance efficacy and specificity. Inhibitors of siderophore biosynthesis targeting both NRPS enzymes and those involved in NRPS-independent pathways of siderophore biosynthesis have been extensively reviewed by Lamb (2015). An alternative approach has been the genetic engineering of the NRPSs to synthesize novel siderophoresa strategy which has been applied to the production of novel pyoverdines .…”

Section: Novel Therapeutic Strategies Targeting Iron Acquisition In Cmentioning

confidence: 99%

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Tyrrell¹,

Callaghan²

2016

Microbiology

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Iron acquisition is vital to microbial survival and is implicated in the virulence of many of the pathogens that reside in the cystic fibrosis (CF) lung. The multifaceted nature of iron acquisition by both bacterial and fungal pathogens encompasses a range of conserved and speciesspecific mechanisms, including secretion of iron-binding siderophores, utilization of siderophores from other species, release of iron from host iron-binding proteins and haemoproteins, and ferrous iron uptake. Pathogens adapt and deploy specific systems depending on iron availability, bioavailability of the iron pool, stage of infection and presence of competing pathogens. Understanding the dynamics of pathogen iron acquisition has the potential to unveil new avenues for therapeutic intervention to treat both acute and chronic CF infections. Here, we examine the range of strategies utilized by the primary CF pathogens to acquire iron and discuss the different approaches to targeting iron acquisition systems as an antimicrobial strategy.

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Section: Novel Therapeutic Strategies Targeting Iron Acquisition In Cmentioning

confidence: 99%

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Tyrrell¹,

Callaghan²

2016

Microbiology

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“…Targeting siderophore uptake via SITs represents a promising anti-fungal strategy, but requires further dissection [104,105]. Recently, the iron-starved microsomal proteome of A. fumigatus has been characterized [16].…”

Section: Iron Starvationmentioning

confidence: 99%

Proteomic analysis of Aspergillus fumigatus – clinical implications

Moloney

Owens

Doyle

2016

Expert Review of Proteomics

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The traits that make A. fumigatus a successful colonizer and pathogen of humans are multi-factorial. Thus, a global investigative approach is required to elucidate the mechanisms utilized by the fungus to cause disease. Expert commentary: In doing so, a better understanding of disease pathology can be achieved with improved therapeutic/diagnostic solutions, thereby improving patient outcome. Proteomic analysis permits such investigations and recent work has yielded insight into these mechanisms.

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“…93–99 The approach of targeting biosynthetic enzymes for inhibitor development shows considerable promise for pathogens that deploy siderophores during host colonization. 97 Success in this area was recently demonstrated in a screen using an assay for the L-ornithine- N 5 -monooxygenase encoded by sidA in A. fumigatus . 100 The crystal structure of the enzyme has been determined and detailed biochemical studies led to the development of a fluorescence polarization binding assay involving a chromophore linked to ADP as a probe for active site binding of small molecules.…”

Section: Targeting Iron Acquisition To Augment Antifungal Therapymentioning

confidence: 99%

Iron acquisition in fungal pathogens of humans

2017

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The devastating infections that fungal pathogens cause in humans are underappreciated relative to viral, bacterial and parasitic diseases. In recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In particular, exciting new work illustrates the importance of iron acquisition from heme and hemoglobin in the virulence of pathogenic yeasts. However, the challenge of establishing how these fungi gain access to hemoglobin in blood and to other sources of heme remains to be fully addressed. Recent studies are also expanding our knowledge of iron uptake in less-well studied fungal pathogens, including dimorphic fungi where new information reveals an integration of iron acquisition with morphogenesis and cell-surface properties for adhesion to host cells. Overall, the accumulating information provides opportunities to exploit iron acquisition for antifungal therapy, and new work highlights the development of specific inhibitors of siderophore biosynthesis and metal chelators for therapeutic use alone or in conjunction with existing antifungal drugs. It is clear that iron-related therapies will need to be customized for specific diseases because the emerging view is that fungal pathogens use different combinations of strategies for iron acquisition in the varied niches of vertebrate hosts.

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Breaking a pathogen's iron will: Inhibiting siderophore production as an antimicrobial strategy

Cited by 88 publications

References 116 publications

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Proteomic analysis of Aspergillus fumigatus – clinical implications

Iron acquisition in fungal pathogens of humans

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