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Direct evidence of iron uptake by the Gram-positive siderophore-shuttle mechanism without iron reduction.

ABSTRACT: Iron is an essential element for all organisms, and microorganisms produce small molecule iron-chelators, siderophores, to efficiently acquire Fe(III). Gram-positive bacteria possess lipoprotein siderophore-binding proteins (SBPs) on the membrane. Some of the SBPs bind both apo-siderophores (iron-free) and Fe-siderophore (iron-chelated) and only import Fe-siderophores. When the SBP initially binds an apo-siderophore, the SBP uses the Gram-positive siderophore-shuttle mechanism (the SBPs exchange Fe(III) from a Fe-siderophore to the apo-siderophore bound to the protein) and/or displacement mechanism (the apo-siderophore bound to the SBP is released and a Fe-siderophore is then bound to the protein) to import the Fe-siderophore. Previously, we reported that the Bacillus cereus SBP, YxeB, exchanges Fe(III) from a ferrioxamine B (FO) to a desferrioxamine B (DFO) bound to YxeB using the siderophore-shuttle mechanism although the iron exchange was indirectly elucidated. Synthetic Cr-DFO (inert metal FO analog) and Ga-DFO (nonreducible FO analog) are bound to YxeB and imported via YxeB and the corresponding permeases and ATPase. YxeB exchanges Fe(III) from FO and Ga(III) from Ga-DFO to DFO bound to the protein, indicating that the metal-exchange occurs without metal reduction. YxeB also binds DFO derivatives including acetylated DFO (apo-siderophore) and acetylated FO (AcFO, Fe-siderophore). The iron from AcFO is transferred to DFO when bound to YxeB, giving direct evidence of iron exchange. Moreover, YxeB also uses the displacement mechanism when ferrichrome (Fch) is added to the DFO:YxeB complex. Uptake by the displacement mechanism is a minor pathway compared to the shuttle mechanism.

SUBMITTER: Fukushima T

PROVIDER: S-EPMC4168784 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Direct evidence of iron uptake by the Gram-positive siderophore-shuttle mechanism without iron reduction.

Fukushima Tatsuya T Allred Benjamin E BE Raymond Kenneth N KN

ACS chemical biology 20140729 9

Iron is an essential element for all organisms, and microorganisms produce small molecule iron-chelators, siderophores, to efficiently acquire Fe(III). Gram-positive bacteria possess lipoprotein siderophore-binding proteins (SBPs) on the membrane. Some of the SBPs bind both apo-siderophores (iron-free) and Fe-siderophore (iron-chelated) and only import Fe-siderophores. When the SBP initially binds an apo-siderophore, the SBP uses the Gram-positive siderophore-shuttle mechanism (the SBPs exchange ...[more]

PMID: 25007174

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Project description:With the increasing reports of community-acquired and nosocomial infection caused by multidrug-resistant Gram-positive pathogens, there is an urgent need to develop new antimicrobial agents with novel antibacterial mechanisms. Here, we investigated the antibacterial activity of the natural product ginkgolic acid (GA) (15:1), derived from Ginkgo biloba, and its potential mode of action against the Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus. The MIC values of GA (15:1) against clinical E. faecalis and S. aureus isolates from China were ≤4 and ≤8 μg/mL, respectively, from our test results. Moreover, GA (15:1) displayed high efficiency in biofilm formation inhibition and bactericidal activity against E. faecalis and S. aureus. During its inhibition of the planktonic bacteria, the antibacterial activity of GA (15:1) was significantly improved under the condition of abolishing iron homeostasis. When iron homeostasis was abolished, inhibition of planktonic bacteria by GA (15:1) was significantly improved. This phenomenon can be interpreted as showing that iron homeostasis disruption facilitated the disruption of the functions of ribosome and protein synthesis by GA (15:1), resulting in inhibition of bacterial growth and cell death. Genetic mutation of ferric uptake regulator (Fur) led to GA (15:1) tolerance in in vitro-induced resistant derivatives, while overexpression of Fur led to increased GA (15:1) susceptibility. Additionally, GA (15:1) significantly decreased the bacterial loads of S. aureus strain USA300 in the lung tissues of mice in a pneumonic murine model. Conclusively, this study revealed an antimicrobial mechanism of GA (15:1) involving cross talk with iron homeostasis against Gram-positive pathogens. In the future, the natural product GA (15:1) might be applied to combat infections caused by Gram-positive pathogens. IMPORTANCE The increasing emergence of infectious diseases associated with multidrug-resistant Gram-positive pathogens has raised the urgent need to develop novel antibiotics. GA (15:1) is a natural product derived from Ginkgo biloba and possesses a wide range of bioactivities, including antimicrobial activity. However, its antibacterial mechanisms remain unclear. Our current study found that the function of ferric uptake regulator (Fur) was highly correlated with the antimicrobial activity of GA (15:1) against E. faecalis and that the antibacterial activity of GA (15:1) could be strengthened by the disruption of iron homeostasis. This study provided important insight into the mode of action of GA (15:1) against Gram-positive bacteria and suggested that GA (15:1) holds the potential to be an antimicrobial treatment option for infection caused by multidrug-resistant Gram-positive pathogens.

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Direct evidence of iron uptake by the Gram-positive siderophore-shuttle mechanism without iron reduction.

Publications

Direct evidence of iron uptake by the Gram-positive siderophore-shuttle mechanism without iron reduction.

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