Development of "induces of β-lactam-susceptibility in MRSA (ILSMR)" and elucidaton of the novel regulatory mechanism

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In order to develop novel effective drugs against infectious diseases caused by MRSA, we attempted to elucidate the mechanism of action of "inducers of β-lactam-susceptibility in MRSA (ILSMR)" and the novel mechanism of drug resistance of MRSA. In the present investigation, expression of mecA and that of penicilllin-binding protein 2' (PBP2') of MRSA, incubated with or without flavone, were analyzed by Northern and Western blottings, respectively. There were no change in mecA mRNA and the protein levels, indicating that the action of the ILSMR flavone is independent of the regularoty mechanism of mecA transcription system. To explore genes which are typically expressed or repressed by the ILSMR effect, cDNA differential hybridization was performed using RNAs extracted from MRSA strain No. 5-10 incubated with or without flavone. We found 26 clones which exhibited some changes in the expression levels under the present experimental conditions. Determination of the sequences and the homology search revealed that vraS and vraR expression were enhanced in the presence of flavone and the two component signal trans-duction system associated with the both genes may play an important role in the induction mechanism of β-lactam-susceptibility in MRSA.We also found that flavone and its derivatives were highly active against systemic infections by MRSA in mice. In particular, TA1101 having no ILSMR effect in vitro revealed that mice were cured by the treatment with binary dose of the substance and a β-lactam antibiotic. It is interesting that such a curing effect of TA1101 was shown when it was orally administered before the mice were infected with MRSA.