Graduation Year

2003

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemistry

Major Professor

Turos, Edward

Keywords

antibiotic, mode of action, sar, drug resistance, staphylococcus

Abstract

N-Methylthio beta-lactams represent a promising new family of antibacterial agents whose in vitro activity is confined largely to Staphylococcus species, including multidrug-resistant forms of S. aureus. Originally developed in the 1980's for use as synthetic intermediates, N-methylthio beta-lactams have recently been shown in these laboratories to possess intriguing biological properties which are addressed in Chapters I-IV. In terms of the antibacterial activities, the structural features and species specificities exhibited by these compounds are unlike those of any existing family of beta-lactam drugs. The lactams seem to exert their effects intracellularly, requiring passage of the bioactive species through the cellular membrane, rather than acting extracellularly on cell wall components in the manner of penicillin and related antibiotics.

The lipophilic nature of these molecules, which lack the polar side chain functionality of all other microbially-active Beta-lactams, suggests the compounds do not target the penicillin binding proteins within bacterial membranes. The most active members of this Beta-lactam class appear to be those bearing an aryl (Ar) substituent at C4 of the ring. The synthesis and structure-activity relationship of these analogues is discussed in Chapter III. Moreover, microscopy and 3H pulse-labeling studies, which are described in Chapter IV, demonstrate that N-methylthio beta-lactams appear to be inhibitors of protein biosynthesis.

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