title: Crystal structures of biapenem and tebipenem complexed with penicillin-binding proteins 2X and 1A from Streptococcus pneumoniae.
abstract: 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. beta-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.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. mototsugu_yamada@meiji.co.jp
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Yamada
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Baba
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Fukuichi
authors.initials: F
authors.lastname: Ohsawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Gomi
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015780:Carbapenems / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D046915:Penicillin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D010458:Peptidyl Transferases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000378:metabolism*; D013845:Thienamycins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D046915:Penicillin-Binding Proteins; D013845:Thienamycins; D047090:beta-Lactams; C072223:PBP 2x protein, Streptococcus; C480727:PBP1a protein, Streptococcus pneumoniae; D010458:Peptidyl Transferases; C500135:tebipenem; C065257:biapenem