with Enhanced Antibacterial Activity against VRE & VRSA

Our efforts in this area culminated to the development of a vancomycin polymers (Chem. Commun. 1999, 1361), dimers (Chem. Commun. 2007, 251-253; with an in vivo activity), and monomer derivatives (Antimicrob. Agents Chemother. 2010, 54, 960; J. Med. Chem. 2010, 53, 2528) with enhanced activity against VRE.
Present research is focused on the mode of action analysis of these glycopeptides (Med. Chem. Commun. 2011, 2, 278-282; ibid. 2012, 3, 691-695; Chem. Eur. J. 2012, 18, 12681-12689).

We recently reported the first synthesis of the VRE/VRSA's depsi-lipid I, a precursor of bacterial cell wall, which can be used for the detailed mode of action analysis (Chem. Eur. J. 2013, 19, 12104).

• KENDOMYCIN

Kendomycin is the relatively new antibiotics with macrocyclic carbon-ring (Takeda Chemical Industry, Japan). A researcher in UK reported its activity against a vancomycin-resistant S. aureus(GISA, Mu50). Our long standing interests on vancomycin-resistance prompted us to initiate synthetic efforts.

(Sengoku, Arimoto, Uemura, Chem. Commun., 2004, 1220; Chem. Lett. 2007, 726-728)

• Pinnaic Acid & Halichlorine

These compounds were isolated by Prof. Uemura (presently at Kanagawa University). More than 15 research groups are currently involved the synthesis of these compounds.
We have accomplished a racemic (Hayakawa, Arimoto, Uemura, Heterocycles, 2003, 441), and an asymmetric total syntheses of pinnaic acid (Xu, Arimoto, Uemura, Angew. Chem. 2007, 47, 5746) and halichlorine (Chem. Asian J. 2013, in press).

• Other synthetic effort includes: Mangicol (Angewante Chemie, Int. Ed. 2004, 43, 81)

The solitary spider wasp Cyphononyx dorsalis is well known to hunt spiders: it uses its stinger to paralyze its prey to feed its larva. This wasp venom was fractionated by bioassay-guided chromatography and so far three proteins were identified. The recombinant arginine kinase-like protein exhibited paralytic activity against spiders.

(Insect Biochem. Mo. Biol. 2007, 278-286.)

Natural toxins with high specificity to their molecular targets have been contributing greatly for chemical biology of ion channels. A huge natural product palytoxin [mw 2680, LD₅₀ value of 15-450 ng/kg against mice], is a typical example, and has an entirely unique function to convert Na/K pump into a non specific ion channel. We have investigated a solution structure of palytoxin using SAXS, and found that it formed an associated dimer of 5 nm length in aqueous solution.

(with Profs. Fujisawa and Uemura;

Org. Biomol. Chem. 2007, 897-899, and inside front cover of OBC, 2007, issue 6)