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Antimicrobial Agents and Chemotherapy, May 2008, p. 1806-1811, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01381-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Lys234Arg Substitution in the Enzyme SHV-72 Is a Determinant for Resistance to Clavulanic Acid Inhibition{triangledown}

Nuno Mendonça,1 Vera Manageiro,1 Frédéric Robin,2,3 M. José Salgado,4 Eugénia Ferreira,1 Manuela Caniça,1* and Richard Bonnet2,3

Antibiotic Resistance Unit, Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal,1 University Clermont1, UFR Médecine, Laboratoire de bactériologie, EA3844, Clermont-Ferrand F-63001, France,2 CHU Clermont-Ferrand, Centre de Biologie, Laboratoire de bactériologie clinique, Clermont-Ferrand F-63003, France,3 Laboratory of Microbiology, Hospital de Santa Maria, Lisbon, Portugal4

Received 25 October 2007/ Returned for modification 14 January 2008/ Accepted 25 February 2008

The new β-lactamase SHV-72 was isolated from clinical Klebsiella pneumoniae INSRA1229, which exhibited the unusual association of resistance to the amoxicillin-clavulanic acid combination (MIC, 64 µg/ml) and susceptibility to cephalosporins, aztreonam, and imipenem. SHV-72 (pI 7.6) harbored the three amino acid substitutions Ile8Phe, Ala146Val, and Lys234Arg. SHV-72 had high catalytic efficiency against penicillins (kcat/Km, 35 to 287 µM–1·s–1) and no activity against oxyimino β-lactams. The concentration of clavulanic acid necessary to inhibit the enzyme activity by 50% was 10-fold higher for SHV-72 than for SHV-1. Molecular-dynamics simulation suggested that the Lys234Arg substitution in SHV-72 stabilized an atypical conformation of the Ser130 side chain, which moved the O{gamma} atom of Ser130 around 3.5 Å away from the key O{gamma} atom of the reactive serine (Ser70). This movement may therefore decrease the susceptibility to clavulanic acid by preventing cross-linking between Ser130 and Ser70.

* Corresponding author. Mailing address: Antibiotic Resistance Unit, National Institute of Health Dr. Ricardo Jorge Av. Padre Cruz, 1649-016 Lisbon, Portugal. Phone and fax: 351.217519246. E-mail: manuela.canica{at}insa.min-saude.pt

{triangledown} Published ahead of print on 3 March 2008.

Antimicrobial Agents and Chemotherapy, May 2008, p. 1806-1811, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01381-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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