N-Methylthio beta-lactam antibacterials: effects of the C3/C4 ring substituents on anti-MRSA activity.
Bioorg Med Chem
; 13(23): 6289-308, 2005 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-16185880
ABSTRACT
N-Thiolated beta-lactams are a new family of antibacterials that inhibit the growth of Staphylococcus bacteria. Unlike other beta-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 C(3) and C(4) 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 C(3)/C(4) 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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01-internacional
Base de dados:
MEDLINE
Assunto principal:
Staphylococcus aureus
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Compostos de Sulfidrila
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Farmacorresistência Bacteriana
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Beta-Lactamas
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Meticilina
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2005
Tipo de documento:
Article