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Siderophore-mediated iron uptake in bacterial infection

A siderophore, mediated technology, applied in the direction of bacteria, antibacterial drugs, medical preparations containing active ingredients, etc., can solve problems such as difficult treatment, difficult treatment and bad treatment

Inactive Publication Date: 2011-09-28
UNIV OF WESTERN ONTARIO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drug resistance in S. aureus infection poses serious treatment difficulties that are likely to get worse unless new therapeutic agents are developed

Method used

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  • Siderophore-mediated iron uptake in bacterial infection
  • Siderophore-mediated iron uptake in bacterial infection
  • Siderophore-mediated iron uptake in bacterial infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Materials and Methods for Examples 2-10

[0061] Bacterial strains, plasmids and growth media. The bacterial strains and plasmids used in this study are described in Table 1. Bacteria were grown at 37°C unless otherwise indicated.

[0062] Table 1. Bacterial strains, plasmids and oligonucleotides used in this study.

[0063]

[0064]

[0065]

[0066] a Abbreviation: AP R 、Cm R 、Em R 、Km R , Lc R and Tet RResistance to ampicillin, chloramphenicol, erythromycin, kanamycin, lincomycin, and tetracycline, respectively; ATCC, American Type Culture Collection.

[0067] b Restriction sites used for cloning of PCR products are underlined.

[0068] Antibiotics were used at the following concentrations: ampicillin (100 μg / mL) and erythromycin (300 μg / mL) for E. coli selection; chloramphenicol (5 μg / mL), tetracycline (10 μg / mL), kanamycin (50 μg / mL), neomycin (50 μg / mL) and erythromycin (3 μg / mL) were used for S. aureus selection. For molecular ...

Embodiment 2

[0076] Example 2: Staphylococcus aureus sbn mutants still produce siderophores

[0077] A S. aureus strain containing a complete deletion of the sbn operon (ie deletion of all genes from sbnA to sbnI) was constructed. In the S. aureus Newman background, the sbn deletion strain is called H1331, whereas in the RN6390 background it is called H1324. When cultured in serum at 37°C, H1331 showed markedly impaired growth compared to wild-type Newman during the first 15 hours of incubation and then eventually grew to a cell density equivalent to Newman's in about 30 hours ( figure 1 ). Analysis of depleted culture supernatants for iron sequestration activity using the chromazurin S assay (Schwyn and Neilands, 1987) from the 35h time point showed comparable siderophore activity between Newman and H1331 ( figure 2 ). Supplementing the serum medium with iron eliminated the growth defect of H1331 ( figure 1 , insert), and suppressed siderophore production in both Newman and H1331 ...

Embodiment 3

[0082] Example 3: A second iron-regulated siderophore biosynthesis locus in S. aureus is also conserved in coagulase-negative S. aureus

[0083] As S. aureus sbn deletion mutants still produce siderophores, additional loci in S. aureus whose products are capable of siderophores synthesis were identified. Examination of available S. aureus genome sequences identified a 4-gene locus that likely encodes siderophore biosynthetic enzymes; in Newman strains, these open reading frames were identified as NWMN_2079-NWMN_2082 ( image 3 ). This locus is identified as sbt, standing for siderophore biosynthesis 2 ( s iderophore b iosynthesis two). The sbt locus is located in the genome immediately upstream of the htsABC operon (NWMN 2078-2076), which encodes a component of the ABC transporter previously thought to transport heme into staphylococcal cells. sbtA divergently transcribes from a probable polycistronic message comprising sbtB-sbtD.

[0084] Unlike the sbn operon, which ...

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Abstract

The present invention relates to methods of inhibiting S. aureus comprising inhibiting siderophore-mediated iron uptake, for example, staphyloferrm-mediated iron uptake Such methods of inhibiting S. aureus include the inhibition of staphyloferrm A- and staphyloferrm B- mediated uptake either by inhibiting expression or activity of staphyloferrm A and B or by inhibiting transport of staphyloferrm A and B The methods as provided would be useful for treating S. aureus infection.

Description

technical field [0001] The present invention relates to iron uptake pathways in infectious bacteria and, in particular, to methods of inhibiting such bacteria using siderophore-mediated iron uptake pathways. Background technique [0002] Almost without exception, iron is an essential nutrient for all microorganisms. Under physiological conditions, iron exists mainly as insoluble ferric hydroxide (Fe3+) and is generally complexed with proteins for transport and storage through animal body fluids. Intracellular iron is carried by ferritins (a phylogenetically ubiquitous globular iron storage protein) and heme-related proteins, whereas serum iron is bound to glycoproteins, particularly transferrin. Increased iron deposition (known as hyposideremia) is an aspect of the innate immune response that further limits iron availability to invading pathogens. This is due to endocytosis of iron-containing glycoproteins (increase of liver-localized ferritin) and limitation of iron relea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/02A61K45/00A61P31/04C07K14/31C12N1/20C12P7/48
CPCC12P13/04A61K31/7088C07K14/31A61P31/04A61P43/00
Inventor D·E·海因里希斯F·比斯利E·维奈斯J·张
Owner UNIV OF WESTERN ONTARIO
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