Effect of metal ions on diphtheria toxin production

Groman, Neal B.; Judge, K.

doi:10.1128/iai.26.3.1065-1070.1979

Cited by 17 publications

(6 citation statements)

References 9 publications

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“…The elevated levels of ionized zinc oxide, exceeding 1,500 mM, in the wound fluid are sufficient to inhibit attachment 57 and growth of S. aureus including methicillinresistant S. aureus 26,58,59 and corynebacteria in vitro. 60 In accordance with our bacteriological findings, zinc oxide also inhibited the growth of S. aureus in experimental wounds. 25,26 However, the mere colonization by these Gram-positive microorganisms is unlikely to be detrimental to wound healing, 61 and the benefit of topical antimicrobials in wound management is unclear.…”

Section: Discussionsupporting

confidence: 89%

A randomized, double‐blind, placebo‐controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision

Ågren

Ostenfeld

Kallehave

et al. 2006

Wound Repair Regeneration

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The purpose of this randomized, double-blind, placebo-controlled multicenter trial was to compare topical zinc oxide with placebo mesh on secondary healing pilonidal wounds. Sixty-four (53 men) consecutive patients, aged 17-60 years, were centrally randomized to either treatment with 3% zinc oxide (n = 33) or placebo (n = 31) by concealed allocation. Patients were followed with strict recording of beneficial and harmful effects including masked assessment of time to complete wound closure. Analysis was carried out on an intention-to-treat basis. Median healing times were 54 days (interquartile range 42-71 days) for the zinc and 62 days (55-82 days) for the placebo group (p = 0.32). Topical zinc oxide increased (p < 0.001) wound fluid zinc levels to 1,540 (1,035-2,265) microM and decreased (p < 0.05) the occurrence of Staphylococcus aureus in wounds. Fewer zinc oxide (n = 3) than placebo-treated patients (n = 12) were prescribed postoperative antibiotics (p = 0.005). Serum-zinc levels increased (p < 0.001) postoperatively in both groups but did not differ significantly between the two groups on day 7. Zinc oxide was not associated with increased pain by the visual analog scale, cellular abnormalities by histopathological examination of wound biopsies, or other harmful effects. Larger clinical trials will be required to show definitive effects of topical zinc oxide on wound healing and infection.

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Section: Discussionsupporting

confidence: 89%

A randomized, double‐blind, placebo‐controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision

Ågren

Ostenfeld

Kallehave

et al. 2006

Wound Repair Regeneration

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“…SitC responds to divalent metal ions other than iron. The production of diphtheria toxin is known to be repressed in a DtxR-dependent manner by iron and various divalent metal cations, including Co 2ϩ , Mn 2ϩ , and Ni 2ϩ (15,39). To investigate whether the sitABC operon is similarly controlled by metal cations, we used a monoclonal antibody raised against SitC (6) to probe immunoblots of the whole-cell proteins of S. epider- Figure 4 shows that SitC production in S. epidermidis is fully repressed by the presence of iron and Mn 2ϩ but unaffected by the presence of Co 2ϩ , Cu 2ϩ , Ni 2ϩ , Zn 2ϩ , or Mg 2ϩ in the growth medium.…”

Section: Resultsmentioning

confidence: 99%

SirR, a Novel Iron-Dependent Repressor in Staphylococcus epidermidis

et al. 1998

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In Staphylococcus epidermidis and Staphylococcus aureus, a number of cell wall-and cytoplasmic membraneassociated lipoproteins are induced in response to iron starvation. To gain insights into the molecular basis of iron-dependent gene regulation in the staphylococci, we sequenced the DNA upstream of the 3-kb S. epidermidis sitABC operon, which Northern blot analysis indicates is transcriptionally regulated by the growth medium iron content. We identified two DNA sequences which are homologous to elements of the Corynebacterium diphtheriae DtxR regulon, which controls, in response to iron stress, for example, production of diphtheria toxin, siderophore, and a heme oxygenase. Upstream of the sitABC operon and divergently transcribed lies a 645-bp open reading frame (ORF), which codes for a polypeptide of approximately 25 kDa with homology to the DtxR family of metal-dependent repressor proteins. This ORF has been designated SirR (staphylococcal iron regulator repressor). Within the sitABC promoter/operator region, we also located a region of dyad symmetry overlapping the transcriptional start of sitABC which shows high homology to the DtxR operator consensus sequence, suggesting that this region, termed the Sir box, is the SirR-binding site. The SirR protein was overexpressed, purified, and used in DNA mobility shift assays; SirR retarded the migration of a synthetic oligonucleotide based on the Sir box in a metal (Fe 2؉ or Mn 2؉ )-dependent manner, providing confirmatory evidence that this motif is the SirR-binding site. Furthermore, Southern blot analysis of staphylococcal chromosomal DNA with the synthetic Sir box as a probe confirmed that there are at least five Sir boxes in the S. epidermidis genome and at least three in the genome of S. aureus, suggesting that SirR controls the expression of multiple target genes. Using a monospecific polyclonal antibody raised against SirR to probe Western blots of whole-cell lysates of S. aureus, S. carnosus, S. epidermidis, S. hominis, S. cohnii, S. lugdunensis, and S. haemolyticus, we identified an approximately 25-kDa cross-reactive protein in each of the staphylococcal species examined. Taken together, these data suggest that SirR functions as a divalent metal cation-dependent transcriptional repressor which is widespread among the staphylococci.

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“…DtxR, like many other metalloregulatory proteins, has a broad metal ion selectivity in vitro (Schmitt and Holmes, 1993; Tao et al ., 1994), but is highly selective for its cognate regulatory ion (iron) in vivo . Measurements of toxin production in the presence of different metal ions indicate that Mn(II) can elicit repression, but only at concentrations 1000‐fold greater than needed for Fe(II) (Groman and Judge, 1979). This difference suggests that other possible activating ions do not accumulate to sufficient levels within the cytosol, or are tightly bound to other molecules, and therefore cannot activate DNA‐binding.…”

Section: Discussionmentioning

confidence: 99%

Origins of metal ion selectivity in the DtxR/MntR family of metalloregulators

Guédon¹,

Helmann²

2003

Molecular Microbiology

100

127

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SummaryCorynebacterium diphtheriae DtxR is an iron-specific repressor of diphtheria toxin expression and iron homeostasis functions. A homologue, MntR, serves as a manganese-specific repressor of Mn(II) uptake in Bacillus subtilis . When expressed in B. subtilis , DtxR regulates gene expression in response to either iron or manganese with comparable sensitivity. Replacement of two amino acids in the metal-sensing site with the corresponding residues from MntR results in a DtxR mutant that is highly selective for Mn(II). However, iron responsiveness can be partially restored in a fur mutant in which iron uptake is derepressed and intracellular iron pools elevated. Conversely, if the putative metal-binding residues in MntR are altered to those in DtxR, the resulting protein responds to both iron and manganese. These results suggest that the composition and geometry of the metal-binding site plays a major role in defining the metal-selectivity in this protein family. However, the broadened selectivity of DtxR when expressed in B. subtilis , and the effects of a fur mutation, demonstrate that cellular milieu also influences metal responsiveness.

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Effect of metal ions on diphtheria toxin production

Cited by 17 publications

References 9 publications

A randomized, double‐blind, placebo‐controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision

A randomized, double‐blind, placebo‐controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision

SirR, a Novel Iron-Dependent Repressor in Staphylococcus epidermidis

Origins of metal ion selectivity in the DtxR/MntR family of metalloregulators

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