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Antimicrobial Agents and Chemotherapy, October 1998, p. 2576-2583, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Roles of Amino Acids 161 to 179 in the PSE-4 &OHgr; Loop in Substrate Specificity and in Resistance to Ceftazidime

Christian Therrien,1 Francois Sanschagrin,1 Timothy Palzkill,2 and Roger C. Levesque1,*

Microbiologie Moléculaire et Génie des Protéines, Sciences de la Vie et de la Santé, Faculté de Médecine, Université Laval, Ste-Foy, Québec, Canada G1K 7P4,1 and Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 770302

Received 2 February 1998/Returned for modification 13 May 1998/Accepted 9 August 1998

The PSE-4 enzyme is a prototype carbenicillin-hydrolyzing enzyme exhibiting high activity against penicillins and early cephalosporins. To understand the mechanism that modulates substrate profiles and to verify the ability of PSE-4 to extend its substrate specificity toward expanded-spectrum cephalosporins, we used random replacement mutagenesis to generate six random libraries from amino acids 162 to 179 in the Omega  loop. This region is known from studies with TEM-1 to be implicated in substrate specificity. It was found that the mechanism modulating ceftazidime hydrolysis in PSE-4 was different from that in TEM-1. The specificity of class 2c carbenicillin-hydrolyzing enzymes could not be assigned to the Omega  loop of PSE-4. Analysis of the percentage of functional enzymes revealed that the hydrolysis of ampicillin was more affected than hydrolysis of carbenicillin by amino acid substitutions at positions 162 to 164 and 165 to 167.

* Corresponding author. Mailing address: Microbiologie Moleculaire et Genie des Protéines, Sciences de la Vie et de la Santé, Faculté de Médecine, Pavillon Charles-Eugène Marchand, Université Laval, Ste-Foy, Quebec, Canada G1K 7P4. Phone: (418) 656-3070. Fax: (418) 656-7176. E-mail: rclevesq{at}rsvs.ulaval.ca.

Antimicrobial Agents and Chemotherapy, October 1998, p. 2576-2583, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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