抄録
Infectious diseases due to antibiotic-resistant bacteria pose a threat to public health around the world. Especially, nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in hospitals have become a serious clinical problem. Therefore, an antibacterial agent is clinically desirable. In the course of our screening system for anti-MRSA antibiotics, we found that a novel cyclic depsipeptide antibiotic, WAP-8294A_2(1) produced by a Gram-negative bacterium Lysobacter sp. showed higher in vivo activity against MRSA. We report the structure and activity of this antibiotic. This antibiotic is composed of Gly, L-Leu, L-Glu, D-Asn, D-Trp, D-threo-β-hydroxyasparagine, N-methyl-D-Phe, N-methyl-L-Val, and two residues of L-Ser, D-Orn, and D-3-hydroxy-7-methyl-octanoic acid. The structure of 1 was determined mainly by 2D NMR experiments including HMBC and ROESY techniques. 1 was as active as vancomycin against MRSA clinical isolates (MIC: 0.78μg/mL) and interestingly, this activity was highly enhanced by the addition of 10% human serum (MIC: <0.1μg/mL). No activity of 1 was observed against Gram-negative bacteria, yeasts and fungi. In vivo efficacies of 1 and vancomycin were assessed in the experimental systemic MRSA infection of mice. The mean ED_<50> values of 1 and vancomycin against nine MRSA strains were 0.38mg/kg and 5.3mg/kg, respectively, indicating that 1 is 14 times more active than vancomycin.
