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Treatment of microbial infections

a technology for microbial infections and infections, applied in the field of microbial infections, can solve the problems of increasing multi-drug resistance (mdr), difficult to eradicate rapid progressive and highly destructive joint diseases, and serious medical problems of hematogenous acquired bacterial arthritis

Inactive Publication Date: 2011-06-23
TRINITY COLLEGE DUBLIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0054]Thus, it will be understood that the recombinant staphylococcal MSCRAMM or MSCRAMM-like protein, or fragment thereof, may have reduced binding with its host ligand or binding with the host ligand may be prevented.
[0114]Thus, immunization with these mutant proteins is expected to, based on the proteins tested, enhance the level of antibodies which recognized both the mutant and wild type protein and to provide for a greater immune response than the wild type protein.

Problems solved by technology

Multiple drug resistance (MDR) is an increasing problem amongst gram positive bacteria, particularly in hospitals.
Hematogenously acquired bacterial arthritis remains a serious medical problem.
This rapidly progressive and highly destructive joint disease is difficult to eradicate.
Initial localized infections of wounds or indwelling medical devices can lead to more serious invasive infections such as septicaemia, osteomyelitis, mastitis and endocarditis.
Vascular grafts, intravenous catheters, artificial heart valves, and cardiac assist devices are thrombogenic and prone to bacterial colonization.
Unfortunately, penicillin-resistant organisms quickly emerged and the need for new antibiotics was paramount.
Once the bacteria have successfully adhered and colonized host tissues, their physiology is dramatically altered and damaging components such as toxins and enzymes are secreted.
Additionally, this document does not demonstrate experimentally whether the binding of the mutant protein to the ligand is reduced and does not provide any supporting immunogenicity data.

Method used

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  • Treatment of microbial infections
  • Treatment of microbial infections
  • Treatment of microbial infections

Examples

Experimental program
Comparison scheme
Effect test

example 1

rClfA A Region Truncates Comprising N1, N2 and N3 (Amino Acids 40-559)

Material and Methods

[0144]Full details of the numeric references in brackets given in the Examples are provided at the end of this section.

Mice

[0145]NMRI mice were obtained from Scanbur BK (Sollentuna, Sweden) and were maintained in the animal facility of the Department of Rheumatology, University of Göteborg, Sweden. Göteborg animal experiment ethical board approved the experiments. They were housed up to 10 animals per cage with a 12 h light-dark cycle, and were fed standard laboratory chow and water ad libitum. The animals were 6 to 16 weeks old at the start of the experiments.

Bacterial Strains

[0146]For infection of animals the S. aureus wildtype strains Newman (14) and LS-1 (11) and constructed derivatives thereof were used. The clfA P336SY338A (clfAPYI) and clfA P336AY338S (clfAPYII) derivatives were constructed in strain Newman and transduced to strain LS-1 (see below). The deletion mutants Newman clfA2::Tn9...

example 2

rClfA A Region Truncate Comprising N2 and N3 (rClfA 221-559)

Materials & Methods:

[0198]The protocols outlined in Example 1 were followed in this example which utilized[0199]rClfA 221-559 (i.e. ClfA A region truncate comprising N2 and N3 corresponding to amino acids 220-559)[0200]rClfAPY221-559; and[0201]BSA.

[0202]There were 15 female NMRI mice per group who were 8 weeks old at start of experiments. In this Example, the constructs used for immunization were ClfA wild type / native N2N3 truncate, ClfA N2N3 truncate with mutation PY as defined in Example 1. BSA was used as the control.

Vaccination with Wild-Type and Mutant Recombinant ClfA

[0203]The mice were immunized with rClfA 221-559, rClfAPY 221-559 or BSA in accordance with the protocol of Example 1.

[0204]Purified rClfA221-559, rClfAPY221-559 (i.e. ClfAPYI recombinant protein A subdomains N2 and N3) or BSA were dissolved in PBS and emulsified 1:1 in Freund's complete adjuvant. Two hundred μl of the emulsion containing 30 μg (=0.79 nmo...

example 3

ClfA A Region Truncate (δ / Delta Latch Truncate)

Materials & Methods:

[0210]The protocols outlined in Example 1 were followed in this example which utilized the following construct:[0211]rClfA 221-531 (i.e. rClfA A region truncate comprising N2 and N3 amino acids 220-559 but without the latching peptide amino acids 532-538 and the subsequent proline-rich residues.

[0212]There were 15 female NMRI mice in the group who were 8 weeks old at start of experiment. In this Example, the above construct was used for immunization. The mice were immunized with the above truncate in accordance with the protocol of Example 1.

Vaccination with Wild-Type and Mutant Recombinant ClfA

[0213]Purified rClfA221-531 was dissolved in PBS and emulsified 1:1 in Freund's complete adjuvant. Two hundred μl of the emulsion containing 0.79 nmol of protein was injected s.c. on day 0. First booster immunization with 0.79 nmol of protein in physiologic saline in incomplete Freund's adjuvant was performed on day 12. Second...

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Abstract

The present invention is directed to improved microbial antigen vaccines, pharmaceutical compositions, immunogenic compositions and antibodies and their use in the treatment of microbial infections, particularly those of bacterial origin, including Staphylococcal origin. Ideally, the present invention is directed to a recombinant staphylococcal MSCRAMM or MSCRAMM-like proteins, or fragment thereof, with reduced binding to its host ligand, for use in therapy.

Description

INTRODUCTION[0001]The present invention relates to improved microbial antigen vaccines, pharmaceutical compositions, immunogenic compositions and antibodies and their use in the treatment of microbial infections, particularly those of bacterial origin, including Staphylococcal origin.[0002]Multiple drug resistance (MDR) is an increasing problem amongst gram positive bacteria, particularly in hospitals. The widespread use of antibiotics and other agents to treat bacterial infections has led to the rapid development of bacteria resistant to the agents and many bacteria have multiple drug resistance. Thus, there is now a need to provided improved therapies for dealing with such drug resistant infections.[0003]Staphylococci are Gram-positive bacteria of spherical shape, usually arranged in grape-like irregular clusters. Some are members of the normal flora of the skin and mucous membranes of humans, others cause suppuration, abscess formation, a variety of pyogenic infections, and even ...

Claims

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Application Information

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IPC IPC(8): A61K39/085C12N15/63C12N1/00A61P37/04A61P31/04
CPCA61K38/00C07K16/1271C07K14/31A61K39/085A61P31/00A61P31/04A61P37/04A61K39/00A61K2039/545A61K2039/55566
Inventor FOSTER, TIMOTHYHIGGINS, JUDYJOSEFSSON, ELISABETGEOGHEGAN, JOANANDERSSON, CARLAKE
Owner TRINITY COLLEGE DUBLIN
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