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Our research group has focused on the discovery of new leads for combination chemotherapy against MRSA. A b-lactam drug imipenem clinically used in hospitals is inactive against MRSA. Microbial culture broths were screened for potentiators of imipenem activity against MRSA. In the course of this screening program, a new compound designated cyslabdan was isolated from the culture broth of “Streptomyces cyslabdanicus” K04-0144. From spectroscopic analyses including NMR, its structure was elucidated to be a labdan-type diterpene connecting to an N-acetylcysteine residue via thioether linkage. Among b-lactam drugs, cyslabdan effectively restored carbapenem activity against MRSA by 500 to 1000 fold, whereas had no such restoration activity with other typical antibiotics (streptomycin, vancomycin, tetracycline and ciprofloxacin). From study of the mechanism of action, cyslabdan was found to be bound to FemA, which is involved in the synthesis of pentaglycine interpeptide bridge of MRSA peptidoglycan. Furthermore, the results of peptidoglycan analysis of cyslabdan-treated MRSA and the effect of cyslabdan on FemA enzymatic activity also supported the conclusion that the primary molecular target of cyslabdan is FemA. Cyslabdan is demonstrated to be the first microbial product which inhibits MRSA FemA. The reason why cyslabdan can restore imipenem activity against MRSA is also discussed.
