N-Methylthio β-lactam antibacterials: Effects of the C3/C4 ring substituents on anti-MRSA activity

N-Thiolated β-lactams are a new family of antibacterials that inhibit the growth of Staphylococcus bacteria. Unlike other β-lactam drugs, these compounds retain their full antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains and operate through a different mode of action. The structural features, which give these lactams their biological activity, have not yet been completely defined. Earlier efforts in our laboratory established that the N-organothio substituent is essential for antimicrobial activity while other groups at C3 and C4 on the lactam ring play a more subtle role. In this present study, we investigate these effects by varying the polar and steric nature of the ring substituents at these two centers. From the data presented herein, it appears that there is a need to balance the lipophilic character of the C3/C4 groups to obtain an optimal anti-MRSA activity. The structure–bioactivity profiles more closely relate to the compound’s ability to penetrate the bacterial cell membrane to sites of action within the cytoplasm rather than to any specific non-bonding interactions with a biological target. Based on these results, a model for the compounds’ mode of action is presented.

This report describes a study of the antibacterial properties of N-methylthio β-lactams 1 as a function of the C3/C4 ring substituents R1, R2, R3, and R4.Figure optionsDownload as PowerPoint slide