Bioorganic and Medicinal Chemistry p. 6289 - 6308 (2005)
Update date:2022-07-30
Topics:
Turos, Edward
Coates, Cristina
Shim, Jeung-Yeop
Wang, Yang
Leslie, J. Michelle
Long, Timothy E.
Reddy, G. Suresh Kumar
Ortiz, Alex
Culbreath, Marci
Dickey, Sonja
Lim, Daniel V.
Alonso, Eduardo
Gonzalez, Javier
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.
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