Penicillin-binding Protein 2x of Streptococcus pneumoniae: Three New Mutational Pathways for Remodelling an Essential Enzyme into a Resistance Determinant
| Autor: | Carlos Contreras-Martel, Mark van der Linden, Barbara Koch, Ilka Zerfaß, Jean-Marie Frère, Patrick Maurer, Jan KRAUß, Regine Hakenbeck |
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| Rok vydání: | 2008 |
| Předmět: |
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Molecular Penicillin binding proteins Cefotaxime Mutant Context (language use) medicine.disease_cause Pneumococcal Infections Protein Structure Secondary beta-Lactam Resistance Serine Structural Biology medicine Humans Penicillin-Binding Proteins Point Mutation Molecular Biology chemistry.chemical_classification Genetics Mutation biology Active site Protein Structure Tertiary Streptococcus pneumoniae Enzyme chemistry Peptidyl Transferases biology.protein medicine.drug |
| Zdroj: | Journal of Molecular Biology. 376:1403-1416 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2007.12.058 |
| Popis: | Mutations in the transpeptidase domain of penicillin-binding protein 2x (PBP2x) of Streptococcus pneumoniae that reduce the affinity to beta-lactams are important determinants of resistance to these antibiotics. We have now analyzed in vitro and in vivo properties of PBP2x variants from cefotaxime-resistant laboratory mutants and a clinical isolate. The patterns of two to four resistance-specific mutations present in each of the proteins, all of which are placed between 6.6 and 24 A around the active site, fall into three categories according to their positions in the three-dimensional structure. The first PBP2x group is characterized by mutations at the end of helix α11 and carries the well-known T550A change and/or one mutation on the surface of the penicillin-binding domain in close contact with the C-terminal domain. All group I proteins display very low acylation efficiencies, ≤ 1700 M − 1 s − 1 , for cefotaxime. The second class represented by PBP2x of the mutant C505 shows acylation efficiencies below 100 M − 1 s − 1 for both cefotaxime and benzylpenicillin and contains the mutation L403F at a critical site close to the active serine. PBP2x of the clinical isolate 669 reveals a third mutational pathway where at least the two mutations Q552E and S389L are important for resistance, and acylation efficiency is reduced for both beta-lactams to around 10,000 M − 1 s − 1 . In each group, at least one mutation is located in close vicinity to the active site and mediates a resistance phenotype in vivo alone, whereas other mutations might exhibit secondary effects only in context with other alterations. |
| Databáze: | OpenAIRE |
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