A battle for iron: host sequestration and Staphylococcus aureus acquisition

Haley, Kathryn P.; Skaar, Eric P.

doi:10.1016/j.micinf.2011.11.001

Cited by 141 publications

(122 citation statements)

References 69 publications

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“…By targeting the bacterial iron metabolism that is vital for the growth, survival, and virulence of virtually all bacteria (23)(24)(25), Def induces starvation and upregulation of iron-acquisition systems (26) while GaPP exploits the latter. By mimicking heme (i.e., iron-protoporphyrin), the preferred iron source of many bacteria (23,27), GaPP is taken up into bacterial cells where it inhibits essential cellular pathways, disrupts the respiratory chain, and induces reactive oxygen species that are toxic to bacteria (28).…”

Section: Discussionmentioning

confidence: 99%

A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity

Richter

Thomas

Claeys

et al. 2017

Antimicrob Agents Chemother

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Many infectious diseases are associated with multidrug-resistant (MDR) bacteria residing in biofilms that require high antibiotic concentrations. While oral drug delivery is frequently ineffective, topical treatments have the potential to deliver higher drug concentrations to the infection site while reducing systemic side effects. This study determined the antibiofilm activity of a surgical wound gel loaded with the iron chelator deferiprone (Def) and the heme analogue gallium-protoporphyrin (GaPP), alone and in combination with ciprofloxacin. Activity against MDR Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Acinetobacter johnsonii biofilms was assessed in the colony biofilm and artificial wound model by enumeration of CFU and correlative light/electron microscopy. While Staphylococcus biofilms were equally susceptible to GaPP and Def-GaPP gels (log 10 reduction of 3.8 and 3.7, respectively), the Def-GaPP combination was crucial for significant activity against P. aeruginosa biofilms (log 10 reduction of 1.3 for GaPP and 3.3 for DefGaPP). When Def-GaPP gel was combined with ciprofloxacin, the efficacy exceeded the activity of the individual compounds. Def-GaPP delivered in a surgical wound gel showed significant antibiofilm activity against different MDR strains and could enhance the gel's wound-healing properties. Moreover, Def-GaPP indicated a potentiation of ciprofloxacin. This antibiofilm strategy has potential for clinical utilization as a therapy for topical biofilm-related infections.KEYWORDS antimicrobial combinations, biofilms, drug delivery, iron metabolism M edical treatments for chronic infectious diseases are typically based on oral delivery of high-dose, long-term antibiotic therapies. Despite the risk for emerging antimicrobial resistance and the potential of side effects (e.g., gastrointestinal disorders, neutropenia, nephrotoxicity), there is a lack of suitable alternatives. Depending on the disease nature and localization, topical treatments can deliver high dosages of antimicrobials directly to an infection site while reducing unwanted systemic effects. Higher drug dosages are particularly needed to combat microbial biofilms (1). The ability of bacteria to form biofilms and establish resistance to antibiotics is a major biomedical threat, adding billions of dollars to health care costs worldwide (1-3). Biofilms are responsible for 80% of microbial infections in humans and are a common cause of chronic infections, including chronic wound and chronic sinus infections (4, 5), with increasing tolerance and subtle resistance mechanisms to antibiotic therapies (6-8).

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Section: Discussionmentioning

confidence: 99%

A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity

Richter

Thomas

Claeys

et al. 2017

Antimicrob Agents Chemother

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“…90% bound to heme, mostly within hemoglobin (52,53). Additional iron sequestration mechanisms are used by the human host during infection to counteract the ability of pathogens to obtain iron (6,29,31,39). The inevitable competition with the host has led to both Gram-positive and Gram-negative bacterial pathogens developing several distinct mechanisms for accessing iron from heme (21,43,50,56,65,74).…”

Section: Discussionmentioning

confidence: 99%

Iron-Regulated Surface Determinant (Isd) Proteins of Staphylococcus lugdunensis

et al. 2012

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bStaphylococcus lugdunensis is the only coagulase-negative Staphylococcus species with a locus encoding iron-regulated surface determinant (Isd) proteins. In Staphylococcus aureus, the Isd proteins capture heme from hemoglobin and transfer it across the wall to a membrane-bound transporter, which delivers it into the cytoplasm, where heme oxygenases release iron. The Isd proteins of S. lugdunensis are expressed under iron-restricted conditions. We propose that S. lugdunensis IsdB and IsdC proteins perform the same functions as those of S. aureus. S. lugdunensis IsdB is the only hemoglobin receptor within the isd locus. It specifically binds human hemoglobin with a dissociation constant (K d ) of 23 nM and transfers heme on IsdC. IsdB expression promotes bacterial growth in an iron-limited medium containing human hemoglobin but not mouse hemoglobin. This correlates with weak binding of IsdB to mouse hemoglobin in vitro. Unlike IsdB and IsdC, the proteins IsdJ and IsdK are not sorted to the cell wall in S. lugdunensis. In contrast, IsdJ expressed in S. aureus and Lactococcus lactis is anchored to peptidoglycan, suggesting that S. lugdunensis sortases may differ in signal recognition or could be defective. IsdJ and IsdK are present in the culture supernatant, suggesting that they could acquire heme from the external milieu. The IsdA protein of S. aureus protects bacteria from bactericidal lipids due to its hydrophilic C-terminal domain. IsdJ has a similar region and protected S. aureus and L. lactis as efficiently as IsdA but, possibly due to its location, was less effective in its natural host.

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“…These proteins, together with other iron-sequestering proteins including lipocalins that sequester iron from bacterial siderophores (Goetz et al, 2002;Fluckinger et al, 2004), play a significant role in iron-targeted nutritional immunity. The battle between host iron sequestration and Staphylococcus aureus iron acquisition typifies these complex relationships, and is detailed in a review by Haley & Skaar (2012).…”

Section: Iron and Cfmentioning

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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A battle for iron: host sequestration and Staphylococcus aureus acquisition

Cited by 141 publications

References 69 publications

A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity

A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity

Iron-Regulated Surface Determinant (Isd) Proteins of Staphylococcus lugdunensis

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

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