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Antimicrobial Agents and Chemotherapy, June 2008, p. 2053-2060, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01456-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Crystal Structures of Biapenem and Tebipenem Complexed with Penicillin-Binding Proteins 2X and 1A from Streptococcus pneumoniae{triangledown}

Mototsugu Yamada,1* Takashi Watanabe,1 Nobuyoshi Baba,1 Yasuo Takeuchi,1,{dagger} Fukuichi Ohsawa,2 and Shuichi Gomi1

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 November 2007/ Returned for modification 16 January 2008/ Accepted 27 March 2008

Biapenem is a parenteral carbapenem antibiotic that exhibits wide-ranging antibacterial activity, remarkable chemical stability, and extensive stability against human renal dehydropeptidase-I. Tebipenem is the active form of tebipenem pivoxil, a novel oral carbapenem antibiotic that has a high level of bioavailability in humans, in addition to the above-mentioned features. β-lactam antibiotics, including carbapenems, target penicillin-binding proteins (PBPs), which are membrane-associated enzymes that play essential roles in peptidoglycan biosynthesis. To envisage the binding of carbapenems to PBPs, we determined the crystal structures of the trypsin-digested forms of both PBP 2X and PBP 1A from Streptococcus pneumoniae strain R6, each complexed with biapenem or tebipenem. The structures of the complexes revealed that the carbapenem C-2 side chains form hydrophobic interactions with Trp374 and Thr526 of PBP 2X and with Trp411 and Thr543 of PBP 1A. The Trp and Thr residues are conserved in PBP 2B. These results suggest that interactions between the C-2 side chains of carbapenems and the conserved Trp and Thr residues in PBPs play important roles in the binding of carbapenems to PBPs.

* 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 7 April 2008.

{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, June 2008, p. 2053-2060, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01456-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Powell, A. J., Tomberg, J., Deacon, A. M., Nicholas, R. A., Davies, C. (2009). Crystal Structures of Penicillin-binding Protein 2 from Penicillin-susceptible and -resistant Strains of Neisseria gonorrhoeae Reveal an Unexpectedly Subtle Mechanism for Antibiotic Resistance. J. Biol. Chem. 284: 1202-1212 [Abstract] [Full Text]  


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