Deferoxamine mesylate enhances virulence of community-associated methicillin resistant Staphylococcus aureus

Arifin, Andrew J.; Hannauer, Mélissa; Welch, Ian; Heinrichs, David E.

doi:10.1016/j.micinf.2014.09.003

Cited by 22 publications

(13 citation statements)

References 12 publications

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“…The dose of DFO administered over the course of the two first days of infection was the same as previously employed by Arifin et. al [59] and corresponded to approximately 50 mg/kg/day, which is comparable to the weight-adjusted dose recommended for use in humans (Hospira).…”

Section: Methodsmentioning

confidence: 80%

“…Previously, it was demonstrated that administration of DFO to S. aureus -infected mice augmented virulence in a systemic model of infection [59]. To examine whether DFO could enhance S. aureus hemB growth in vivo , systemic infections were performed using mice that were administered DFO intraperitoneally.…”

Section: Resultsmentioning

confidence: 99%

“…It is well accepted that siderophore production by S. aureus contributes to bacterial fitness during infection [56, 79], however, siderophore expression can be heterogenous and influenced by the niche occupied by the bacteria [80]. That accessibility to iron in the host is indeed limited, despite the ability of WT S. aureus to produce siderophores, is evidenced by the observation that intraperitoneal injection of DFO significantly enhances bacterial replication and virulence in vivo [59], as it does for other pathogens such as Yersinia enterocolitica [81]. The in vivo role or significance of SA and SB in the context of the hemB mutation in S. aureus is, at present, unclear given that elimination of the sfa and sbn loci does not further attenuate the bacterial load in organs infected with the hemB SCV.…”

Section: Discussionmentioning

confidence: 99%

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Heme-dependent siderophore utilization promotes iron-restricted growth of the Staphylococcus aureus hemB small colony variant

Batko

Flannagan

Guariglia-Oropeza

et al. 2021

Preprint

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The ability to acquire iron is essential for Staphylococcus aureus to cause infection. Respiration deficient S. aureus small colony variants (SCVs) frequently cause persistent infections, which necessitates they too acquire iron. How SCVs obtain iron remains unknown and so here we addressed this outstanding question by creating a stable hemB mutant in S. aureus USA300 strain LAC. The mutant, auxotrophic for hemin, was assessed for its ability to grow under iron-restriction and with various iron sources. The hemB SCV utilizes exogenously supplied heme but was attenuated for growth under conditions of iron starvation. RNA-seq analyses showed that both WT S. aureus and the hemB mutant sense and respond to iron starvation, however, growth assays show that the hemB mutant is defective for siderophore-mediated iron acquisition. Indeed, the hemB SCV demonstrates limited utilization of endogenous staphyloferrin B or exogenously provided staphyloferrin A, Desferal, and epinephrine, which enabled the SCV to sustain only minimal growth in iron deplete media. Direct measurement of intracellular ATP in hemB and WT S. aureus revealed that both strains can generate comparable levels of ATP during exponential growth suggesting defects in ATP production cannot account for the inability to efficiently utilize siderophores. Defective siderophore utilization by hemB bacteria was also evident in vivo. Indeed, the administration of Desferal failed to promote hemB bacterial growth in vivo, in contrast to WT, in every organ analyzed except for the murine kidney where growth was enhanced. In support of the hypothesis that S. aureus accesses heme in kidney abscesses, in vitro analyses revealed that increased heme availability enables hemB bacteria to utilize siderophores for growth when iron availability is restricted. Taken together, our data support the conclusion that heme is not only used as an iron source itself, but as a nutrient that promotes utilization of siderophore-iron complexes.

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Section: Methodsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Heme-dependent siderophore utilization promotes iron-restricted growth of the Staphylococcus aureus hemB small colony variant

Batko

Flannagan

Guariglia-Oropeza

et al. 2021

Preprint

Self Cite

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“…Recently our group has shown that mice treated with DFO had increased USA300 burden in the livers and kidneys, a phenomenon attributed to the ability of the bacteria to scavenge DFO‐bound iron via the Fhu uptake system (Arifin et al ., ). Here we have extended these findings to demonstrate the essential role of IruO in enhanced S. aureus virulence in the presence of systemic DFO (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…As we reported earlier in this study, an iruO mutation obviates DFO-mediated growth enhancement of USA300 under conditions of iron starvation. Moreover, we have recently reported that DFO (also known as Desferal®), a drug used clinically to treat patients suffering from iron overload, exacerbates USA300 infection in mice (Arifin et al, 2014). Knowing this, we decided to test whether iruO was an essential component of the DFO-mediated exacerbation of S. aureus USA300 virulence.…”

Section: Mutation Of Iruo Obviates Dfo-mediated Exacerbation Of Usa30mentioning

confidence: 99%

Involvement of reductases IruO and NtrA in iron acquisition by Staphylococcus aureus

Hannauer

Arifin

Heinrichs

2015

Molecular Microbiology

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SummaryTo obtain host iron, Staphylococcus aureus secretes siderophores staphyloferrin A (SA) or staphyloferrin B (SB), and accesses heme iron through use of ironregulated surface determinant proteins. While iron transport in S. aureus is well documented, there is scant information about proteins required to access iron from complexes in the cytoplasm. In vitro studies identified a pyridine nucleotide-disulfide oxidoreductase, named IruO, as an electron donor for the heme monooxygenases IsdG and IsdI, promoting heme degradation. Here, we show that an iruO mutant was not debilitated for growth on heme, suggesting involvement of another reductase. NtrA is an ironregulated nitroreductase and, as with the iruO mutant, a ntrA mutant grew on heme comparable with wild type (WT). In contrast, a iruO ntrA double mutant was severely debilitated for growth on heme, a phenotype that was complemented by expression of either iruO or ntrA in trans, demonstrating their overlapping role in heme-iron utilization. Contrasting the involvement of multiple reductases for heme iron utilization, ntrA was shown essential for iron utilization using SA, although not SB or other siderophores tested, and an iruO mutant was incapable of deferoxamine-mediated growth. Accordingly, virulence of WT S. aureus, but not an iruO mutant, was enhanced in mice receiving deferoxamine.

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Sideromycins as Pathogen-Targeted Antibiotics

Wencewicz

Miller

2017

Topics in Medicinal Chemistry

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Deferoxamine mesylate enhances virulence of community-associated methicillin resistant Staphylococcus aureus

Cited by 22 publications

References 12 publications

Heme-dependent siderophore utilization promotes iron-restricted growth of the Staphylococcus aureus hemB small colony variant

Heme-dependent siderophore utilization promotes iron-restricted growth of the Staphylococcus aureus hemB small colony variant

Involvement of reductases IruO and NtrA in iron acquisition by Staphylococcus aureus

Sideromycins as Pathogen-Targeted Antibiotics

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