Synthetic Study on Globomycins toward the Development of New Antibiotics

The increasing incidence of antibiotic resistance has brought a new, sense, of urgency to the discovery and development of antibacterial drugs. Globomycin (1a), a 19-membered cyclic depsipeptide, shows potent antibacterial activity against Gram-negative bacteria and has been proven to be a specific inhibitor of signal peptidase II, a prolipoprotein-processing enzyme. Although 1a is an important compound for studies on lipoprotein biosynthesis, its structure has been ambiguous for more than 20 years since its discovery. We have succeeded in determining the absolute structure of 1a by X-ray analysis, and developed the synthetic route for this compound and its various analogues. As a result of SAR studies, one of the analogues showed more potent activity against Gram-negative bacteria than 1a and also exhibited antibacterial activity against MRSA. In addition, a conformational analysis of 1a was performed by high-temperature molecular dynamics simulation in combination with H-1 NMR analysis to elucidate the conformations in solution. The relative ratio of the major and minor isomers present, which differs depending on the solvent, was derived from their relative energy differences obtained by the conformational analysis. Details are described.