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Antimicrobial Agents and Chemotherapy, August 2004, p. 2905-2910, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2905-2910.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Characterization of a Cephamycin-Hydrolyzing and Inhibitor-Resistant Class A ß-Lactamase, GES-4, Possessing a Single G170S Substitution in the -Loop

Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Tokyo,¹ Central Clinical Laboratory, Kagoshima Municipal Hospital, Kagoshima,³ Program in Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan²

Received 26 August 2003/ Returned for modification 19 November 2003/ Accepted 5 April 2004

The nosocomial spread of six genetically related Klebsiella pneumoniae strains producing GES-type ß-lactamases was found in a neonatal intensive care unit, and we previously reported that one of the six strains, strain KG525, produced a new ß-lactamase, GES-3. In the present study, the molecular mechanism of cephamycin resistance observed in strain KG502, one of the six strains described above, was investigated. This strain was found to produce a variant of GES-3, namely, GES-4, which was responsible for resistance to both cephamycins (cefoxitin MIC, >128 µg/ml) and ß-lactamase inhibitors (50% inhibitory concentration of clavulanic acid, 15.2 ± 1.7 µM). The GES-4 enzyme had a single G170S substitution in the -loop region compared with the GES-3 sequence. This single amino acid substitution was closely involved with the augmented hydrolysis of cephamycins and carbapenems and the decreased affinities of ß-lactamase inhibitors to GES-4. A cloning experiment and sequencing analysis revealed that strain KG502 possesses duplicate bla_GES-4 genes mediated by two distinct class 1 integrons with similar gene cassette configurations. Moreover, the genetic environments of the bla_GES-4 genes found in strain KG502 were almost identical to that of bla_GES-3 in strain KG525. From these findings, these two phenotypically different strains were suggested to belong to a clonal lineage. The bla_GES-4 gene found in strain KG502 might well emerge from a point mutation in the bla_GES-3 gene harbored by its ancestor strains, such as strain KG525, under heavy antibiotic stress in order to acquire extended properties of resistance to cephamycins and carbapenems.

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