The Texas A&m University System

Inhibitex, Inc.

The Uab Research Foundation

Universitá Degli Studi Di Pavia

Yi Xu

Magnus Höök

Slawomir Lukomski

Joseph M Patti

Magnus A Hook

Jeff T Hutchins

Andrea Hall

Narayana Sthanam

Maria G Bowden

Karthe Ponnuraj

Jouko V Sillanpaa

Magnus A O Hook

Pietro Speziale

Paul Domanski

Pratiksha Patel

Livia Visal

Fabrizia Casolini

A bioinformatic method for identifying and isolating proteins and peptides with MSCRAMM&#xae;-like characteristics from Gram positive bacteria, such asandbacteria, and proteins and peptides obtained thereby are provided which can be utilized in methods to prevent and treat infections caused by Gram-positive bacteria. The method involves identifying from sequence information those proteins with a putative C-terminal LPXTG (SEQ ID NO:1) cell wall sorting signal and other structural similarities to MSCRAMM&#xae; proteins having the LPXTG-anchored cell wall proteins. The MSCRAMM&#xae; proteins and immunogenic regions therein that are identified and isolated using the present invention may be useful in the diagnosis, treatment or prevention of Gram positive bacterial infections.

Bioinformatic method for identifying surface-anchored proteins from gram-positive bacteria and proteins obtained thereby

The present invention provides recombinant triple helical proteins or collagen-like proteins comprising a prokaryotic protein or one or more domains of a prokaryotic protein comprising a collagen-like peptide sequence of repeated Gly-Xaa-Yaa triplets and, optionally, one or more domains from a mammalian collagen. Also provided are expression vectors and host cells containing the expression vectors to produce these recombinant proteins and methods of producing the same. Additionally, antibodies are provided that are directed against a recombinant collagen-like protein that, preferably, binds an integrin. Furthermore, a method of screening for potential therapeutic compounds that inhibit the integrin-binding or integrin-interacting activities of recombinant collagen-like proteins.

Prokaryotic collagen-like proteins and uses thereof

A bioinformatic method is provided for identifying and isolating proteins with MSCRAMM&#xae;&#x2014;like characteristics from Gram positive bacteria, such asandbacteria, which can then be utilized in methods to prevent and treat infections caused by Gram-positive bacteria. The method involves identifying from sequence information those proteins with a putative C-terminal LPXTG (SEQ ID NO:1) cell wall sorting signal and other structural similarities to MSCRAMM&#xae; proteins having the LPXTG-anchored cell wall proteins. The MSCRAMM&#xae; proteins and immunogenic regions therein that are identified and isolated using the present invention may be used to generate antibodies useful in the diagnosis, treatment or prevention of Gram positive bacterial infections.

The present invention provides recombinant triple helical proteins or collagen-like proteins comprising a prokaryotic protein or one or more domains of a prokaryotic protein comprising a collagen-like peptide sequence of repeated Gly-Xaa-Yaa triplets and, optionally, one or more domains from a mammalian collagen. Also provided are expression vectors and host cells containing the expression vectors to produce these recombinant proteins and methods of production for the same. Additionally, antibodies are provided that are directed against a recombinant collagen-like protein that, preferably, binds an integrin. Furthermore, a method of screening for potential therapeutic compounds that inhibit the integrin-binding or -interacting activities of recombinant collagen-like proteins.

Antibodies to the CNA protein and to other regions from the collagen binding domain, including domain CNA19, are provided, and antibodies produced in this manner have been shown to be cross reactive to bothandbacteria and which can thus be used in the prevention and treatment of infections caused by both of these types of bacteria. In addition, medical instruments can be treated using the antibodies of the invention in order to reduce or eliminate the possibility of their becoming infected or further spreading the infection. In particular, the proteins are advantageous because they are cross-reactive and may thus be administered to patients so as to reduce or prevent severe infection by staphylococcal bacteria of more than one species. Antibodies generated in this manner have also been shown to exhibit displacement activity and can thus be utilized advantageously in methods wherein these antibodies will be administered to patients having pre-existing staphylococcal infections because of the ability to displace bacterial proteins from binding sites on the extracellular matrix. Finally, a method of identifying, isolating and utilizing displacing antibodies is also provided.

Cross-reactive displacing antibodies from collagen-binding proteins and method of identification and use

Isolated peptide sequences and proteins containing these sequences are provided which are useful in the prevention and treatment of infection caused by Gram-positive bacteria. The peptide sequences have been shown to be highly conserved motifs in the surface proteins of Gram-positive bacteria, and these consensus sequences include amino acid sequences such as LPXTG (SEQ ID NO:13), ALKTGKIDIIISGMTSTPERKK (SEQ ID NO:14), VEGAWEKPVAEAYLKQN (SEQ ID NO:15), and EYAGVDIDLAKKIAK (SEQ ID NO:16). By virtue of the highly conserved regions, the sequences and the proteins including these sequences can be utilized to generate antibodies which can recognize these highly conserved motifs and the proteins containing them and thus be useful in the treatment or prevention of a wide range of infections caused by Gram-positive bacteria.

Surface proteins from gram-positive bacteria having highly conserved motifs and antibodies that recognize them

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Houston, TX, United States of America

Yi Xu