Objective
In Streptococcus pneumoniae, strains resistant to beta-lactams are usually affected in their penicillin binding proteins (PBP). The relationship between resistance levels and affected PBP has been studied using deoxyribonucleic acid (DNA) mediated transformation and cloning.
A wild type strain has been transformed by DNA from the highest resistant strain C506 and selected at several levels of cefotaxime. It was found that at least 3 unlinked genes are required to obtain a strain which resists to a level similar to that of the donor strain. As DNA molecules are 10-20 Kb long, the genes are separated by larger distances. Thus there is no evidence of any operon.
Strains identical for their serotype, antibiotic resistance and electrophoretic type can be readily separated by pulse gel electrophoresis (PGE). Therefore this technology provides an excellent genetic footprint to determine if 2 isolates recently derived from the same parent.
PBP 3 is strongly labelled by benzyl penicillin in the R6 strain. By itself PBP 3 did not afford resistance but it increased by a factor of 2 all resistance levels in strains already mutated in PBP 2x or 2a. It is proposed that PBP 3 has an indirect effect on resistance in binding strongly beta-lactam that competes with other proteins more essential for resistance such as PBP 2x.
In order to understand the molecular basis of interaction of PBPs with beta-lactam antibiotics the 3-dimensional structure is being determined. A soluble derivative of PBP 2x has been constructed by molecular genetic techniques, and attempts to crystallize it were successful. Cysteine residues are being introduced by site directed mutagenesis in order to be able to resolve the structure.
Other investigations have been carried out into:
non PBP mutations involved in cefotaxime resistance;
mutations in piperacillin resistant laboratory mutants;
penicillin resistance in clinical isolates of S. pneumoniae;
functional analysis of PBPs.
During development of beta-lactam resistance of S. Pneumoniae (intrinsic resistance), multiple mutations in several high
molecular weight PBP lead to decresed penicillin-affinity.
The combination of classical and molecular genetic analysis
should lead to an understanding of the pathway of penicillin-resistance, involving the identification of genes contributing to resistance, and characterizing the regions in the PBP that are important for interaction with beta-lactam antibiotics.
Staphylococcal mutants in PBP will be isolated in order to
disclose their physiological role. Chemical analysis of the
murein synthesized by resistant mutants containing mutated
PBP will help to understand the actual function of PBP and the relationship between these proteins in different Gram positive cocci.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics mutation
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs antibiotics
- natural sciences mathematics pure mathematics mathematical analysis functional analysis
- medical and health sciences basic medicine pharmacology and pharmacy drug resistance antibiotic resistance
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Coordinator
14195 BERLIN
Germany
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