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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 {Omega}-Loop

Jun-ichi Wachino,1,2 Yohei Doi,1 Kunikazu Yamane,1 Naohiro Shibata,1 Tetsuya Yagi,1 Takako Kubota,3 and Yoshichika Arakawa1*

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 {Omega}-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 blaGES-4 genes mediated by two distinct class 1 integrons with similar gene cassette configurations. Moreover, the genetic environments of the blaGES-4 genes found in strain KG502 were almost identical to that of blaGES-3 in strain KG525. From these findings, these two phenotypically different strains were suggested to belong to a clonal lineage. The blaGES-4 gene found in strain KG502 might well emerge from a point mutation in the blaGES-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.

* Corresponding author. Mailing address: Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan. Phone: 81-42-561-0771, ext. 500. Fax: 81-42-561-7173. E-mail: yarakawa{at}nih.go.jp.

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.



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