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JAC Advance Access published online on August 27, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn339
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Natural D240G Toho-1 mutant conferring resistance to ceftazidime: biochemical characterization of CTX-M-43

Giuseppe Celenza1, Carla Luzi1, Massimiliano Aschi2, Bernardetta Segatore1, Domenico Setacci1, Cristina Pellegrini1, Chiara Forcella1, Gianfranco Amicosante1 and Mariagrazia Perilli1,*

1 Department of Biomedical Sciences and Technologies, University of L'Aquila, L'Aquila, Italy 2 Department of Chemistry, Chemical Engineering and Materials, University of L'Aquila, L'Aquila, Italy

Received 1 February 2008; returned 29 April 2008; revised 3 July 2008; accepted 29 July 2008

* Corresponding author. Tel: +39-0862-433489; Fax: +39-0862-433433; E-mail: perilli{at}univaq.it

Objectives: The aim of this article is biochemical and kinetic characterization of CTX-M-43, a natural Asp-240->Gly mutant of CTX-M-44 (ex Toho-1), from a clinical isolate of Acinetobacter baumannii isolated in a Bolivian hospital.

Methods: Steady-state kinetic parameters (Km and kcat) were determined for a large pattern of substrates. Analysis of inactivators and transient inactivators was performed to determine the efficiency of acylation (k+2/K) and the deacylation constant (k+3). Molecular modelling of Michaelis complex of ceftazidime, cefotaxime and ceftibuten, obtained from molecular mechanics calculations, was carried out.

Results: CTX-M-43 showed a general increase in affinity towards all cephalosporins tested, with respect to CTX-M-44. Carbapenems acted as inactivators with a good acylation efficiency for meropenem and ertapenem and significant deacylation constant for imipenem. MICs of imipenem obtained at a higher bacterial inoculum of recombinant Escherichia coli were increased.

Conclusions: Kinetic data and molecular modelling of Michaelis complex confirmed that Asp-240->Gly allows a better accommodation of the bulky C7β aminothiazol-oxyimino substituent, resulting in a general increase in the enzyme affinity towards oxyimino cephalosporins. The ascertained potentialities of CTX-M-type enzymes, supported by the kinetic data and the behaviour of the recombinant E. coli at different bacterial inocula towards carbapenems, make a possible evolution of those enzymes towards a carbapenemase activity plausible.

Key Words: Acinetobacter baumannii , antibiotic resistance , CTX-M-type enzymes , class A


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