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Antimicrobial Agents and Chemotherapy, May 2004, p. 1454-1460, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1454-1460.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of a Mutation at Position 167 of CTX-M-19 in Ceftazidime Hydrolysis

Soichiro Kimura,1 Masaji Ishiguro,2* Yoshikazu Ishii,1* Jimena Alba,1 and Keizo Yamaguchi1

Department of Microbiology, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 1438540,1 Suntory Institute for Bioorganic Research, 1-1-1 Wakayamadai, Mishima-gun, Osaka 6188503, Japan2

Received 15 July 2003/ Returned for modification 28 September 2003/ Accepted 30 December 2003

CTX-M-19 is a recently identified ceftazidime-hydrolyzing extended-spectrum ß-lactamase, which differs from the majority of CTX-M-type ß-lactamases that preferentially hydrolyze cefotaxime but not ceftazidime. To elucidate the mechanism of ceftazidime hydrolysis by CTX-M-19, the ß-lactam MICs of a CTX-M-19 producer, and the kinetic parameters of the enzyme were confirmed. We reconfirmed here that CTX-M-19 is also stable at a high enzyme concentration in the presence of bovine serum albumin (20 µg/ml). Under this condition, we obtained more accurate kinetic parameters and determined that cefotaxime (kcat/Km, 1.47 x 106 s–1 M–1), cefoxitin (kcat/Km, 62.2 s–1 M–1), and aztreonam (kcat/Km, 1.34 x 103 s–1 M–1) are good substrates and that imipenem (k+2/K, 1.20 x 102 s–1 M–1) is a poor substrate. However, CTX-M-18 and CTX-M-19 exhibited too high a Km value (2.7 to 5.6 mM) against ceftazidime to obtain their catalytic activity (kcat). Comparison of the MICs with the catalytic efficiency (kcat/Km) of these enzymes showed that some ß-lactams, including cefotaxime, ceftazidime, and aztreonam showed a similar correlation. Using the previously reported crystal structure of the Toho-1 ß-lactamase, which belongs to the CTX-M-type ß-lactamase group, we have suggested characteristic interactions between the enzymes and the ß-lactams ceftazidime, cefotaxime, and aztreonam by molecular modeling. Aminothiazole-bearing ß-lactams require a displacement of the aminothiazole moiety due to a severe steric interaction with the hydroxyl group of Ser167 in CTX-M-19, and the displacement affects the interaction between Ser130 and the acidic group such as carboxylate and sulfonate of ß-lactams.

* Corresponding author. Mailing address for Y. Ishii: Department of Microbiology, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 1438540, Japan. Phone: 81-3-3762-4151, ext. 2396. Fax: 81-3-5493-5415. E-mail: yoishii{at}med.toho-u.ac.jp. Mailing address for M. Ishiguro: Suntory Institute for Bioorganic Research, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 6188503, Japan. Phone: 81-75-962-3742. Fax: 81-75-962-2115. E-mail: ishiguro{at}sunbor.or.jp.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1454-1460, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1454-1460.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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