Abstract:(2017) In vivo analysis of staphylococcus aureus-infected mice reveals differential temporal and spatial expression patterns of fhuD2. Infection and Immunity, 85(10), e00270-17. (doi:10.1128/IAI.00270-17) This is the author's final accepted version.There may be differences between this version and the published version. Staphylococcus aureus is an opportunistic human pathogen and a major cause of invasive 21 infections such as bacteremia, endocarditis, pneumonia and wound infections. FhuD2 is a 22
“…This evidence was consistent with DIBI sequestering host Fe within wounds or on the mucosal surfaces of the nares, i.e., host Fe supplies that would otherwise have been available to support S. aureus infection. The in vivo results are especially significant given the recent demonstration of S. aureus upregulating one of its key iron acquisition systems during experimental infection ( Bacconi et al, 2017 ) revealing the bacterium is forced to compete continuously for host Fe during the course of infection. The previous finding that various Fe acquisition genes are upregulated in S. aureus while colonizing the nares ( Chaves-Moreno et al, 2016 ) provides further evidence that host Fe availability is important for staphylococcal growth in vivo and that effective sequestration of host iron might suppress nares colonization and other infections.…”
Section: Discussionmentioning
confidence: 99%
“…For our DIBI/antibiotic interaction studies, we also deliberately provided only a sub-inhibitory amount of DIBI so as to ensure a physiological condition of Fe-restricted growth, i.e., growth restricted but not fully arrested. This physiological state of Fe-restricted growth could also have clinical relevance to infection noting that S. aureus has been shown to respond to in vivo Fe restriction through upregulation of its Fe acquisition mechanisms throughout the entire course of infection ( Chaves-Moreno et al, 2016 ; Bacconi et al, 2017 ).…”
Section: Discussionmentioning
confidence: 99%
“…Staphylococcus aureus is very adept with iron acquisition being able to access host transferrin, lactoferrin and heme iron sources, produces its own siderophores and is also able to access xenosiderophores including deferoxamine ( Hammer and Skaar, 2011 and Haley and Skaar, 2012 ). The recent demonstration that during experimental infection there is upregulation of the S. aureus FhuD2 iron acquisition receptor which binds hydroxamate xenosiderophores such as deferoxamine ( Bacconi et al, 2017 ) is significant. Additionally, various other siderophore Fe acquisition genes are upregulated in S. aureus while colonizing the nares ( Chaves-Moreno et al, 2016 ).…”
DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in vitro in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of Staphylococcus aureus from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities. Sensitivity to DIBI was similar for both antibiotic-resistant and -sensitive isolates, including hospital- and community-acquired (United States 300) MRSA. DIBI inhibition was primarily bacteriostatic in nature at low concentration and was reversible by addition of Fe. DIBI also exhibited in vivo anti-infective activity in two distinct MRSA ATCC43300 infection and colonization models in mice. In a superficial skin wound infection model, topical application of DIBI provided a dose-dependent suppression of infection along with reduced wound inflammation. Intranasal DIBI reduced staphylococcal burden by >2 log in a MRSA nares carriage model. DIBI was also examined for its influence on antibiotic activities with a reference isolate ATCC6538, typically utilized to assess new antimicrobials. Sub-bacteriostatic concentrations of DIBI resulted in Fe-restricted growth and this physiological condition displayed increased sensitivity to GEN, CIP, and VAN. DIBI did not impair antibiotic activity but rather it enhanced overall killing. Importantly, recovery growth of survivors that typically followed an initial sub-MIC antibiotic killing phase was substantially suppressed by DIBI for each of the antibiotics examined. DIBI has promise for restricting staphylococcal infection on its own, regardless of the isolate’s animal source or antibiotic resistance profile. DIBI also has potential for use in combination with various classes of currently available antibiotics to improve their responses.
“…This evidence was consistent with DIBI sequestering host Fe within wounds or on the mucosal surfaces of the nares, i.e., host Fe supplies that would otherwise have been available to support S. aureus infection. The in vivo results are especially significant given the recent demonstration of S. aureus upregulating one of its key iron acquisition systems during experimental infection ( Bacconi et al, 2017 ) revealing the bacterium is forced to compete continuously for host Fe during the course of infection. The previous finding that various Fe acquisition genes are upregulated in S. aureus while colonizing the nares ( Chaves-Moreno et al, 2016 ) provides further evidence that host Fe availability is important for staphylococcal growth in vivo and that effective sequestration of host iron might suppress nares colonization and other infections.…”
Section: Discussionmentioning
confidence: 99%
“…For our DIBI/antibiotic interaction studies, we also deliberately provided only a sub-inhibitory amount of DIBI so as to ensure a physiological condition of Fe-restricted growth, i.e., growth restricted but not fully arrested. This physiological state of Fe-restricted growth could also have clinical relevance to infection noting that S. aureus has been shown to respond to in vivo Fe restriction through upregulation of its Fe acquisition mechanisms throughout the entire course of infection ( Chaves-Moreno et al, 2016 ; Bacconi et al, 2017 ).…”
Section: Discussionmentioning
confidence: 99%
“…Staphylococcus aureus is very adept with iron acquisition being able to access host transferrin, lactoferrin and heme iron sources, produces its own siderophores and is also able to access xenosiderophores including deferoxamine ( Hammer and Skaar, 2011 and Haley and Skaar, 2012 ). The recent demonstration that during experimental infection there is upregulation of the S. aureus FhuD2 iron acquisition receptor which binds hydroxamate xenosiderophores such as deferoxamine ( Bacconi et al, 2017 ) is significant. Additionally, various other siderophore Fe acquisition genes are upregulated in S. aureus while colonizing the nares ( Chaves-Moreno et al, 2016 ).…”
DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in vitro in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of Staphylococcus aureus from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities. Sensitivity to DIBI was similar for both antibiotic-resistant and -sensitive isolates, including hospital- and community-acquired (United States 300) MRSA. DIBI inhibition was primarily bacteriostatic in nature at low concentration and was reversible by addition of Fe. DIBI also exhibited in vivo anti-infective activity in two distinct MRSA ATCC43300 infection and colonization models in mice. In a superficial skin wound infection model, topical application of DIBI provided a dose-dependent suppression of infection along with reduced wound inflammation. Intranasal DIBI reduced staphylococcal burden by >2 log in a MRSA nares carriage model. DIBI was also examined for its influence on antibiotic activities with a reference isolate ATCC6538, typically utilized to assess new antimicrobials. Sub-bacteriostatic concentrations of DIBI resulted in Fe-restricted growth and this physiological condition displayed increased sensitivity to GEN, CIP, and VAN. DIBI did not impair antibiotic activity but rather it enhanced overall killing. Importantly, recovery growth of survivors that typically followed an initial sub-MIC antibiotic killing phase was substantially suppressed by DIBI for each of the antibiotics examined. DIBI has promise for restricting staphylococcal infection on its own, regardless of the isolate’s animal source or antibiotic resistance profile. DIBI also has potential for use in combination with various classes of currently available antibiotics to improve their responses.
“…Other studies have shown that staphylococcal growth and turnover are high during both human and murine nares carriage with active bacterial replication in the nose (18). DIBI restricts iron supply to S. aureus isolates impairing their growth (12), and DIBI's iron sequestration activity in the nares is supported by the reported upregulated bacterial expression of IsdA, a cell wall component indicative of iron-limited conditions (18), as well as the overall upregulation of iron acquisition systems during nares carriage (19,20). Our results suggest that iron supply to S. aureus isolates within the nares is a key determinant for establishment and maintenance of carriage and that DIBI appears to aid natural host iron-withdrawal mechanisms to suppress carriage.…”
Methicillin-resistant Staphylococcus aureus (MRSA) opportunistic infections are a major health burden. Decolonization of hospitalized patients with mupirocin (MUP) has reduced the incidence of infection but has led to MUP resistance. DIBI is a developmental-stage anti-infective agent that sequesters bacterial iron and bolsters innate host iron-withdrawal defenses. Clinical isolates possessing low, high, or no MUP resistance all had similarly high susceptibilities to DIBI. Intranasal DIBI reduced nares bacterial burdens in mice to the same extent as MUP. No resistance was found after exposure to DIBI.
“…4 ). Consistent with these various studies, S. aureus has been shown to upregulate its iron acquisition mechanisms during growth in the nares (Chaves-Moreno et al 2016 ) and during systemic infection (Bacconi et al 2017 ). Fig.…”
Section: Antibiotic Resistance and Microbial Iron Needsmentioning
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