Natural Variants of the KPC-2 Carbapenemase have Evolved Increased Catalytic Efficiency for Ceftazidime Hydrolysis at the Cost of Enzyme Stability

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The absence of new antibiotics combined with the emergence of antibiotic-resistance enzymes like KPC-2 that can inactivate most β-lactam antibiotics has resulted in a longer duration of medical treatment, higher costs of medical care, and increased mortality. In recent years, a number of amino acid sequence variants of KPC-2 have been identified in clinical isolates worldwide suggesting continued evolution of resistance in KPC-2. In this study we have characterized nine clinically isolated variants of KPC-2 (KPC-3 to -11) that differ from the initial KPC-2 isolate by one to two amino acids. The KPC variants confer increased resistance to the antibiotic ceftazidime as compared to KPC-2. This increase in resistance is correlated with improved ability of the variant enzymes to hydrolyze the antibiotic. Additionally, the changes associated with increased ceftazidime hydrolysis also reduce the thermal stability of the enzyme, indicating the mutations that assist catalysis come with a cost on the overall stability of the enzyme. The high thermal stability of KPC-2 allows destabilizing mutations that enhance catalysis to accumulate while the enzyme retains a folded, functional structure. Thus, the high stability of KPC-2 provides an evolutionary advantage to acquire multiple mutations and retain function as compared to other β-lactamase enzymes.

Vyšlo v časopise: Natural Variants of the KPC-2 Carbapenemase have Evolved Increased Catalytic Efficiency for Ceftazidime Hydrolysis at the Cost of Enzyme Stability. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004949
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004949

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