Combination Therapy of Murine Mucormycosis or Aspergillosis with Iron Chelation, Polyenes, and Echinocandins

Ibrahim, Ashraf S.; Gebremariam, Teclegiorgis; Luo, Guojie; Fu, Yue; French, Samuel W.; Edwards, John E.; Spellberg, Brad

doi:10.1128/aac.01577-10

Cited by 54 publications

(43 citation statements)

References 26 publications

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“…We show that iron chelators have differential effects on the establishment and further development of A. fumigatus biofilms, a finding that is consistent with previous reports of A. fumigatus growing planktonically (10,11). We found that DFM at high concentrations stimulated biofilm formation and development in a manner similar to that with the supplementation of the medium with FeCl 3 .…”

Section: Discussionsupporting

confidence: 81%

“…In vivo studies have shown that the choice of chelator is crucial. DFM therapy has proven to be detrimental in models of mucormycosis and, to a lesser degree, of aspergillosis (8,11,27,28). However, the use of DFS or DFP has been shown to limit fungal growth in vivo (8,29).…”

Section: Discussionmentioning

confidence: 99%

“…Previous data indicate that iron chelators can inhibit the planktonic conidial growth of A. fumigatus in vitro (9,10). This has also been shown in murine models to serve as a treatment for aspergillosis or mucormycosis in combination with other antifungals (11). However, some iron chelators have been shown to enhance conidial growth (10), which makes the identification of therapeutic chelators especially important.…”

mentioning

confidence: 99%

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Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm

Nazik

Penner

Ferreira

et al. 2015

Antimicrob Agents Chemother

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e Iron acquisition is crucial for the growth of Aspergillus fumigatus. A. fumigatus biofilm formation occurs in vitro and in vivo and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl 3 , or FeCl 3 alone. A preformed biofilm was exposed to DFP with or without FeCl 3 . The DFP and DFS MIC 50 against planktonic A. fumigatus was 1,250 M, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of <2,500 M. By XTT testing, DFM concentrations of <1,250 M had no effect, whereas 2,500 M increased biofilms forming in A. fumigatus or preformed biofilms (P < 0.01). DFP at 156 to 2,500 M inhibited biofilm formation (P < 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 M DFP plus any concentration of FeCl 3 was lower than that in the controls (P < 0.05 to 0.001). FeCl 3 at >625 M reversed the DFP inhibitory effect (P < 0.05 to 0.01), but the reversal was incomplete compared to the controls (P < 0.05 to 0.01). For preformed biofilms, DFP in the range of >625 to 1,250 M was inhibitory compared to the controls (P < 0.01 to 0.001). FeCl 3 at >625 M overcame inhibition by 625 M DFP (P < 0.001). FeCl 3 alone at >156 M stimulated biofilm formation (P < 0.05 to 0.001). Preformed A. fumigatus biofilm increased with 2,500 M FeCl 3 only (P < 0.05). In a strain survey, various susceptibilities of biofilms of A. fumigatus clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy for A. fumigatus, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed.A spergillus fumigatus, the ubiquitous saprophytic mold, frequently causes respiratory tract infections, including invasive pulmonary aspergillosis and allergic bronchopulmonary aspergillosis (1). A. fumigatus disease occurs most frequently in immunocompromised individuals, such as bone marrow transplant and other neutropenic patients, solid organ transplant recipients (2), and in those with cystic fibrosis (1, 3), chronic granulomatous disease, or chronic obstructive pulmonary disease (1, 4). Despite therapeutic advances in the development and administration of antifungals, mortality from A. fumigatus infection remains high (5).A. fumigatus has shown, in vivo and in vitro, the ability to form biofilms, or complex aggregates of organisms embedded within a polymer-rich extracellular matrix, which demonstrate increased antimicrobial resistance (32). Thus, there is a need for other therapeutic methods with mechanisms that d...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm

Nazik

Penner

Ferreira

et al. 2015

Antimicrob Agents Chemother

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“…The iron chelator desferasirox in combination with liposomal amphotericin B in a murine model of invasive aspergillosis resulted in a significant decrease in fungal burden and enhanced survival compared with placebotreated mice . However, other dual-and triple-therapy combinations with desferasirox worsened outcomes (Ibrahim et al, 2011). Therefore, it as yet unclear whether combining iron chelators with conventional antifungals will have any future in the clinical treatment of invasive aspergillosis.…”

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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“…Deferiprone and deferasirox have been successfully used to treat mucormycosis and aspergillosis in mice (61)(62)(63)(64) and human patients (65)(66)(67). Collectively, these findings and our data indicate that zinc and iron chelators do not interfere with other key metabolic processes of the host and can be a promising treatment option.…”

Section: Figmentioning

confidence: 49%

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

Laskaris

Atrouni

Calera

et al. 2016

Antimicrob Agents Chemother

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f Aspergillus fumigatus can infect immunocompromised patients, leading to high mortality rates due to the lack of reliable treatment options. This pathogen requires uptake of zinc from host tissues in order to successfully grow and cause virulence. Reducing the availability of that micronutrient could help treat A. fumigatus infections. In this study, we examined the in vitro effects of seven chelators using a bioluminescent strain of A. fumigatus. 1,10-Phenanthroline and N,N,N=,N=-tetrakis(2-pyridylmethyl) ethane-1,2-diamine (TPEN) proved to be the chelators most effective at inhibiting fungal growth. Intraperitoneal administration of either phenanthroline or TPEN resulted in a significant improvement in survival and decrease of weight loss and fungal burden for immunosuppressed mice intranasally infected with A. fumigatus. In vitro both chelators had an indifferent effect when employed in combination with caspofungin. The use of TPEN in combination with caspofungin also significantly increased survival compared to that when using these drugs individually. Our results suggest that zinc chelation may be a valid strategy for dealing with A. fumigatus infections and that both phenanthroline and TPEN could potentially be used either independently or in combination with caspofungin, indicating that their use in combination with other antifungal treatments might also be applicable.A spergillus fumigatus is a widespread soil-dwelling fungal saprotroph (1). It is one of the most ubiquitous fungal species with airborne conidia, and it is estimated that all humans inhale several hundred conidia each day (2). These are completely innocuous to immunocompetent hosts. However, the conidia are able to develop and cause invasive pulmonary aspergillosis (IPA) in immunocompromised individuals (3). This disease is difficult to treat, with a mortality rate of 45.6% (4). Commonly used drug treatment options include triazoles such as voriconazole, which inhibit ergosterol synthesis, amphotericin B, which binds to ergosterol and thus results in increased permeability of the cell membrane, and echinocandins such as caspofungin, which inhibit glucan synthesis (5).Both fungal and bacterial pathogens require cations to grow within their hosts and utilize specialized mechanisms in order to obtain them (6). Zinc is considered essential for all organisms, including pathogens (7). The average concentration of free Zn 2ϩ in human serum is 0.08 M, which is about 150 times lower than the minimal concentration required for A. fumigatus to grow optimally in a defined liquid medium (8). A. fumigatus possesses three genes, zrfA, zrfB, and zrfC, encoding plasma membrane zinc transporters (8). The zrfA and zrfB genes are required for zinc uptake in acidic Zn-limited environments (7), while zrfC is required for zinc uptake in alkaline environments (9) The zrfC gene is primarily responsible for zinc acquisition within a host's lungs and is required for virulence; zrfA and zrfB contribute to fungal pathogenesis to a lesser extent than zrfC and are not r...

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Combination Therapy of Murine Mucormycosis or Aspergillosis with Iron Chelation, Polyenes, and Echinocandins

Cited by 54 publications

References 26 publications

Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm

Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm

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

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

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