Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1995-09-07
1998-06-23
Jones, W. Gary
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 912, 435 911, 435 71, 435 72, 435 732, 435 7021, 4353201, 435 691, 4241301, 4241411, 4241501, 4241921, 4241851, 536 237, 536 231, 536 243, 536 2432, 530300, 530350, C12Q 168, C07H 2104, C07H 2102, C07K 1528
Patent
active
057703612
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the polypeptides associated with the expression of a resistance to antibiotics of the glycopeptide family, this resistance being of a type inducible by vancomycin and not inducible by teicoplanin, particular in the Gram-positive bacteria, in particular in the family of the Gram-positive cocci. The invention also relates to a nucleotide sequence coding for these polypeptides. It also relates to the use of these polypeptides and their nucleotide sequence as agents for the in vitro detection of resistance to glycopeptides. Among the Gram-positive cocci, the invention relates more particularly to the enterococci, the streptococci and the staphylococci.
The glycopeptides, which include vancomycin and teicoplanin, are antibiotic inhibitors of the synthesis of the bacterial cell wall. These antibiotics are very much used for the treatment of severe infections due to Gram-positive cocci (enterococci, streptococci and staphylococci) in particular in cases of allergy and resistance to the penicillins.
Up to 1986 vancomycin proved to be efficacious against almost all strains of enterococci.
The activity of the glycopeptides depends on the formation of a complex between the antibiotic and the peptidoglycan precursors more than on their direct interaction with enzymes of cell wall metabolism. In particular, it has been observed that the glycopeptides bind to the terminal D-alanyl-D-alanine (D-ala-D-ala) residues of the peptidoglycan precursors.
Several phenotypes of resistance to the glycopeptides have been demonstrated; in particular, strains resistant to a high level of glycopeptides and strains resistant to low concentration levels.
By strain resistant to a high level is meant a strain of bacteria, in particular a strain of Gram-positive cocci, for which the minimal inhibitory concentrations (MIC) of vancomycin and teicoplanin are higher than 32 and 8 .mu.g/ml, respectively. The MIC of vancomycin towards strains with low-level resistance are included between 8 and 32 .mu.g/ml. The VanB phenotype is characterized by a resistance inducible by vancomycin but not inducible by teicoplanin. Once induced, this resistance may exist against different glycopeptides, in particular against vancomycin and/or teicoplanin, and at variable levels.
The strains of enterococci corresponding to the VanB phenotype (class B) are in particular strains of E. faecalis and E faecium.
Al-Obed S et al. (FEMS Microbiology Letters 70 (1990) 101-106) have thus compared the resistance proteins to glycopeptides, inducible by vancomycin, in four strains of Enterococci, and have deduced from their comparison the existence of three types of proteins, one of these types being present in the E. faecium strain resistant to low levels of vancomycin. According to the authors of this publication, a protein of molecular weight of about 39.5 kDa is induced in the strains with low-level resistance and this resistance is linked to induction by vancomycin. These strains were also reported to exhibit a resistance to teicoplanin, also induced by vancomycin.
According to Al-Obeid et al., this protein of 39.5 kDa is present in multiple forms but the nature of this multiplicity has not been studied. According to these authors there might exist a structural specificity depending an the species of bacteria concerned and the level Of resistance, which needs to be confirmed.
In this publication Al-Obeid et al. described 11 amino acids of the N-terminal sequence of the protein of 39.5 kDa and observed that this sequence exhibited about 70% homology with many membrane proteins of prokaryotic or eukaryotic origin having diverse functions. According to the authors this comparison did not allow the possible function of the protein to be established. Finally, Al-Obeid et al. noticed that other proteins are induced, although to a lesser degree.
The invention relates to peptides, polypeptides or proteins implicated in the expression of a resistance to antibiotics of the glycopeptide family and in particular to vancomycin and/or teicoplanin as well as nuc
REFERENCES:
Bowie et al. Science 247: 1306-1310 1990.
Dutka Malen et al. Gene 112: 53-58 1992.
Dutka Malen et al.Mol. Gen.364-367 1990.
Al-Obeid et al. FEMS Microbiol. Letts 70:101-106 1990.
Arthur Michel
Courvalin Patrice
Dutka-Malen Sylvie
Evers Stefan
Institut Pasteur
Jones W. Gary
Rees Dianne
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