Shuichi Gomi

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. 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.

Volatile Aroma Constituents of Three Labiatae Herbs Growing Wild in the Karakoram-Himalaya District and Their Antifungal Activity by Vapor Contact

Abstract Ethyl acetate extracts from the flowers and leaves of Perovskia ahrotanoides Karel., Nepeta juncea Benth. and Thymus linearis Benth. growing wild at 2000–3500 m a.s.l. in the Karakoram-Himalaya district were analyzed by GC/MS. The majorvolatile constituents were 1,8-cineole (24.4–27.1%) and α-pinene (18.2–23.2%) for P. abrotanoides, and nepetalactone (71.8%) for N.juncea. Two chemotypes of T. linearis were found in different area, a thymol/carvacrol type in the areas of Hunza and Rupal Valley, and a geraniol/geranyl acetate type in the area of Rakaposhi Valley. Herbs and their major constituents of N.juncea and T. linearis showed potent antifungal activity by vapor contact, but those of P. abrotanoides showed no significant activity.

SF2446, NEW BENZO[α]NAPHTHACENE QUINONE ANTIBIOTICS

New antibiotics SF2446A1, A2, A3, B1 and B2 have been isolated from the culture of Streptomyces sp. SF2446 and antibiotic SF2446B3 has been obtained by methanolysis of SF2446B1 or B2. SF2446A1, A2 and B1 showed strong inhibitory activities against mycoplasmas and Gram-positive bacteria. Empirical molecular formulae of antibiotics SF2446-A1, A2, A3, B1, B2 and B3 were determined to be C34H35NO15, C26H21NO11, C34H35NO14, C34H35NO14 and C26H21NO10, respectively.

Isolation and synthesis of 2″-N-formimidoylistamycins A and B, new istamycin components

Abstract Two new istamycin components have been isolated from culture filtrates of Streptomyces tenjimariensis. Their structures were suggested to be 2″-N-formimidoylistamycins A and B by spectral analysis, and confirmed by synthesis starting from istamycins A0 and B0, respectively.

A chiral synthesis of 3,5,7-tri-O-benzyl-1,4,6-trideoxy-4,6-di-C-methyl-keto-l-ido-2-heptulose, a synthetic segment of the C-1–C-6 portion of erythronolide A

Abstract 3,6-Dideoxy-1,2-O-isopropylidene-3-C-methyl-α- d -glucofuranose (9) was prepared from methyl 4,6-O-benzylidene-3-deoxy-3-C-methyl-α- d -glucopyranoside via 3-deoxy-1,2-O-isopropylidene-3-C-methyl-α- d -glucofuranose (5) in 61% yield. The key intermediates, 3,5,6-trideoxy-1,2-O-isopropylidene-3-C-methyl-5-C-methylene-α- d -xylo-hexofuranose (13) and 3,5-dideoxy-1,2-O-isopropylidene-3-C-methyl-5-C-methylene-α- d -xylo-hexofuranose (21) were prepared from 9 and 5, respectively. Hydroboration of 13, followed by treatment with alkaline hydrogen peroxide, afforded a 4:1 mixture of 3,5-dideoxy-1,2-O-isopropylidene-3,5-di-C-methyl-β- l -idofuranose (14) and the α- d -gluco epimer (15) in 85% yield. Homogeneous hydrogenation of 21 with chlorotris(triphenylphosphine)rhodium(I) gave a 6.4:1 mixture of 15 and 14. Homogeneous hydrogenation of 1,6-anhydro-3,5-dideoxy-3-C-methyl-5-C-methylene-β- d -xylo-hexofuranose, prepared from 21, afforded exclusively the 1,6-anhydro compound 17, which could be derived from 14. Both 14 and 17 were converted into the diethyl dithioacetal, from which the title compound was synthesized, in 4 steps, in 50% yield.