Synthesis of pacidamycin analogues via an Ugi-multicomponent reaction.

The second-generation synthesis of 3'-hydroxypacidamycin D (2) has been accomplished via an Ugi-four component reaction at a late stage of the synthesis. This approach provided ready access to a range of analogues including diastereomers of the diaminobutylic acid residue and hybrid-type analogues of mureidomycins. Biological evaluations of these analogues indicated that the stereochemistry at the diaminobutylic acid residue has a crucial impact on both the MraY biochemical inhibition and whole-cell antibacterial activity.

Mode of action of Van-M-02, a novel glycopeptide inhibitor of peptidoglycan synthesis, in vancomycin-resistant bacteria.

Van-M-02, a novel glycopeptide, was revealed to exert potent activities against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA). A crude assay system was then used to study the mode of action of Van-M-02 as a peptidoglycan synthesis model of both vancomycin-susceptible and -resistant strains. The results suggested that Van-M-02 inhibits the synthesis of lipid intermediates irrespective of their termini. This inhibitory activity may contribute to the anti-VRE and anti-VRSA activities observed.

9-Oxime-3-ketolides: modification at the C-11,12-diol moiety and antibacterial activities against key respiratory pathogens.

In the search for new types of ketolide antibiotics active against key respiratory pathogens including erythromycin-resistant strains, we conducted an extensive study on the modification at the C-11,12-diol moiety of 9-oxime-3-ketolide derivatives. Among the derivatives prepared, compound 6 with carbonate at the C-11,12 position was found to have potent antibacterial activities against erythromycin-resistant Staphylococcus aureus as well as other erythromycin-susceptible strains.

Novel antibacterial macrolides: synthesis of 15-membered diolides.

Novel 15-membered macrolides possessing the dilactone skeleton, diolides 13a and 13b, have been synthesized in our research program aimed at finding new antibacterial macrolides. Key strategic elements of the approach include the ring-expanding reaction of 13-membered dilactones, prepared from erythromycin A (Ery-A), to 15-membered dilactones via intramolecular translactonization. The absolute configuration at the regenerated C-8 position of the new diolides was determined by chemical transformation, leading to the corresponding lactam analogues, whose stereochemistry is known in the literature. For further confirmation, X-ray analysis was performed. The X-ray structure determination of 13a revealed a backbone conformation similar to that of Ery-A. Novel 15-membered diolide 13a and the 11,12-diol 18 exhibited antibacterial activities comparable to that of Ery-A.