Structure-activity relationships of 2-thioisocephem against methicillin-resistant Staphylococcus aureus.

Recently, methicillin-resistant Staphylococcus aureus (MRSA), which is a major pathogen along with Pseudomonas aeruginosa which is resistant to most commercially available antibiotics, has been causing serious problems in hospitals1'2*. Arbekacin, used in the clinical treatment of MRSAinfections, has been reported to be ineffective against certain MRSA3).Probably the only chemotherapeutic drug to which MRSA-resistant strains have not yet arisen is vancomycin4). However, the slow cytokilling activity5) and side effects6) of vancomycin hinder its effective treatment toward MRSAinfections7*. Therefore, as it is critical to develop new cephem antibiotics with higher killing activity against MRSAand fewer side effects than vancomycin, we have been investigating how to obtain more effective antibiotics against MRSAthat show a broad spectrum of antibacterial activity. To this end, we have synthesized 2-thioisocephem compounds with various substituents introduced into the 3and 7-positions. In this communication, we report that anti-MRSA activity was increased, not unexpectedly, by combined modification of 2-thioisocephem with aminothiazol oxime-substituents at the C-7 position and linkage pattern at the C-3 position. The derivatives of 2-thioisocephem (TOC-compounds) were obtained from Otsuka Chemical Co., Ltd. Minimuminhibitory concentration (MIC) was determined by the 2-fold serial agar dilution method with approximately 106CFU/mlof test organism after incubation for 18 hours at 37°C on Muller-Hinton agar (Difco). S. aureus FDA 209 P, Enterococcus faecalis ATCC-12968, Esche-