title: N-Methylthio beta-lactam antibacterials: effects of the C3/C4 ring substituents on anti-MRSA activity.
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.
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, 33620, USA. eturos@shell.cas.usf.edu
authors.forename: Edward
authors.initials: E
authors.lastname: Turos
authors.forename: Cristina
authors.initials: C
authors.lastname: Coates
authors.forename: Jeung-Yeop
authors.initials: JY
authors.lastname: Shim
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: J Michelle
authors.initials: JM
authors.lastname: Leslie
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Long
authors.forename: G Suresh Kumar
authors.initials: GS
authors.lastname: Reddy
authors.forename: Alex
authors.initials: A
authors.lastname: Ortiz
authors.forename: Marci
authors.initials: M
authors.lastname: Culbreath
authors.forename: Sonja
authors.initials: S
authors.lastname: Dickey
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Lim
authors.forename: Eduardo
authors.initials: E
authors.lastname: Alonso
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D008712:Methicillin / Q000494:pharmacology*; D008745:Methylation; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013438:Sulfhydryl Compounds; D047090:beta-Lactams; D008712:Methicillin