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Antimicrobial Agents and Chemotherapy, May 2001, p. 1343-1348, Vol. 45, No. 5
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.5.1343-1348.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Plasmid-Encoded Metallo-beta -Lactamase (IMP-6) Conferring Resistance to Carbapenems, Especially Meropenem

Hisakazu Yano,1,2,* Akio Kuga,1 Ryoichi Okamoto,1 Hidero Kitasato,1 Toshimitsu Kobayashi,2 and Matsuhisa Inoue1

Department of Microbiology, School of Medicine and Environmental Infectious Disease, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 228-8555,1 and Department of Otolaryngology, Nagasaki University School of Medicine, Nagasaki 852-8501,2 Japan

Received 3 July 2000/Returned for modification 20 August 2000/Accepted 30 January 2001

In 1996, Serratia marcescens KU3838 was isolated from the urine of a patient with a urinary tract infection at a hospital in northern Japan and was found to contain the plasmid pKU501. Previously, we determined that pKU501 carries blaIMP and the genes for TEM-1-type beta -lactamases as well as producing both types of beta -lactamases (H. Yano, A. Kuga, K. Irinoda, R. Okamoto, T. Kobayashi, and M. Inoue, J. Antibiot. 52:1135-1139, 1999). pKU502 is a recombinant plasmid that contains a 1.5-kb DNA fragment, including the metallo-beta -lactamase gene, and is obtained by PCR amplification of pKU501. The sequence of the metallo-beta -lactamase gene in pKU502 was determined and revealed that this metallo-beta -lactamase gene differed from the gene encoding IMP-1 by one point mutation, leading to one amino acid substitution: 640-A in the base sequence of the IMP-1 gene was replaced by G, and Ser-196 was replaced by Gly in the mature enzyme. This enzyme was designated IMP-6. The strains that produced IMP-6 were resistant to carbapenems. The MICs of panipenem and especially meropenem were higher than the MIC of imipenem for these strains. The kcat/Km value of IMP-6 was about sevenfold higher against meropenem than against imipenem, although the MIC of meropenem for KU1917, which produced IMP-1, was lower than that of imipenem, and the MIC of panipenem was equal to that of imipenem. These results support the hypothesis that IMP-6 has extended substrate profiles against carbapenems. However, the activity of IMP-6 was very low against penicillin G and piperacillin. These results suggest that IMP-6 acquired high activity against carbapenems, especially meropenem, via the point mutation but in the process lost activity against penicillins. Although IMP-6 has reduced activity against penicillins due to this point mutation, pKU501 confers resistance to a variety of antimicrobial agents because it also produces TEM-1-type enzyme.

* Corresponding author. Mailing address: Department of Otolaryngology, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. Phone: 81-95-849-7350. Fax: 81-95-849-7352. E-mail: d300042c{at}stcc.nagasaki-u.ac.jp.

Antimicrobial Agents and Chemotherapy, May 2001, p. 1343-1348, Vol. 45, No. 5
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.5.1343-1348.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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