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Antimicrobial Agents and Chemotherapy, November 2007, p. 3902-3907, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00743-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Crystal Structure of Cefditoren Complexed with Streptococcus pneumoniae Penicillin-Binding Protein 2X: Structural Basis for Its High Antimicrobial Activity{triangledown}

Mototsugu Yamada,1* Takashi Watanabe,1 Takako Miyara,1 Nobuyoshi Baba,1 Jun Saito,1 Yasuo Takeuchi,1,{dagger} and Fukuichi Ohsawa2

Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567,1 R & D Planning & Management, Meiji Seika Kaisha, Ltd., 2-4-16 Kyobashi, Chuo-ku, Tokyo 104-8002, Japan2

Received 8 June 2007/ Returned for modification 10 July 2007/ Accepted 16 August 2007

Cefditoren is the active form of cefditoren pivoxil, an oral cephalosporin antibiotic used for the treatment of respiratory tract infections and otitis media caused by bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, and methicillin-susceptible strains of Staphylococcus aureus. ß-Lactam antibiotics, including cefditoren, target penicillin-binding proteins (PBPs), which are membrane-associated enzymes that play essential roles in the peptidoglycan biosynthetic process. To envision the binding of cefditoren to PBPs, we determined the crystal structure of a trypsin-digested form of PBP 2X from S. pneumoniae strain R6 complexed with cefditoren. There are two PBP 2X molecules (designated molecules 1 and 2) per asymmetric unit. The structure reveals that the orientation of Trp374 in each molecule changes in a different way upon the formation of the complex, but each forms a hydrophobic pocket. The methylthiazole group of the C-3 side chain of cefditoren fits into this binding pocket, which consists of residues His394, Trp374, and Thr526 in molecule 1 and residues His394, Asp375, and Thr526 in molecule 2. The formation of the complex is also accompanied by an induced-fit conformational change of the enzyme in the pocket to which the C-7 side chain of cefditoren binds. These features likely play a role in the high level of activity of cefditoren against S. pneumoniae.

* Corresponding author. Mailing address: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. Phone: 81-45-541-2521. Fax: 81-45-543-9771. E-mail: mototsugu_yamada{at}meiji.co.jp

{triangledown} Published ahead of print on 27 August 2007.

{dagger} Present address: Food and Health R & D Labs., Meiji Seika Kaisha, Ltd., 5-3-1 Chiyoda, Sakado, Saitama 350-0289, Japan.

Antimicrobial Agents and Chemotherapy, November 2007, p. 3902-3907, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00743-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yamada, M., Watanabe, T., Baba, N., Takeuchi, Y., Ohsawa, F., Gomi, S. (2008). Crystal Structures of Biapenem and Tebipenem Complexed with Penicillin-Binding Proteins 2X and 1A from Streptococcus pneumoniae. Antimicrob. Agents Chemother. 52: 2053-2060 [Abstract] [Full Text]  


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