Biol. Pharm. Bull. 30(2) 287—290 (2007)

(VRE) are very serious problems because of the resistance against not only vancomycin but also many types of antimicrobials. Although enterococci are less virulent, they cause nosocomial infections. VRE was noted from the U.K. and France at first, and then they have become one of the most important nosocomial pathogens worldwide. In the case of the United States, the percentage of VRE in enterococci isolated at intensive care units (ICUs) was 0.4% in 1989, but it was raised up to 28.5% in 2003. Of the strains belonging to the enterococcal species, Enterococcus faecalis and E. faecium are common isolates from human. Among the clinical isolates of enterococcal species, E. faecalis accounts for 80—90% and the rest is mainly E. faecium. The strains of VRE are mainly E. faecalis and E. faecium. In the case of the treatment for infections caused by enterococci, it is one of the most popular methods to use aminoglycosides together with inhibitors of cell wall synthesis such as b-lactams although enterococci are intrinsically resistant to aminoglycosides. Nonetheless, in the cases of infection by highly resistant enterococci against aminoglycosides (for example, MIC of gentamicin is equal or more than 500 mg/ml, or MIC of streptomycin is equal or more than 2000 mg/ml), use of this treatment is limited and it is very difficult to treat patients in such cases. Because many strains of enterococci, methicillin-resistant Staphylococcus aureus (MRSA) and others are resistant against many antimicrobial agents, it is urgently necessary to develop new drugs or new methods effective on such multidrug resistant bacteria. We have been trying to discover inhibitors of drug resistance systems in bacteria. Inhibitors of drug resistance mechanisms seem to be valuable, because they should make resistant bacteria sensitive to drugs. Until now, we and other groups have reported many compounds that potentiated activity of antimicrobial agents against drug-resistant bacteria. For example, corilagin, tellimagrandin I, epicatechin gallate, epigallocatechin gallate or many flavonoids potentiated antibacterial activity of b-lactams against methicillin-resistant Staphylococcus aureus (MRSA). Baicalein potentiated activities of tetracycline and b-lactams against MRSA, 5 -methoxyhydonocarpin inhibited NorA pump in S. aureus and MC-207,110 (phenylalanine arginine bnaphthylamide, PAbN) and its relatives potentiated some types of antimicrobials that are substrates of one of multidrug efflux pumps, MexAB-OprM of Pseudomonas aeruginosa or AcrAB-TolC of Escherichia coli and Enterobacter aerogenes. Regarding to VRE, allicin, which potentiated activity of vancomycin against VRE, and [10]gingerol and some detergents, such as sodium dodecyl sulfate (SDS) and Triton X-100, which potentiated some antimicrobials including aminoglycosides against enterococci have been reported. During the course of our studies, we found that a crude extract from sage leaves reduced the MICs of aminoglycosides (potentiated the antimicrobial activity of aminoglycosides) against VRE. We isolated the effective compound and identified it as carnosol.