Michael J. Szymonifka

Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate beta-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we demonstrate these agents inhibit peptidoglycan synthesis. Because SAV1754 is essential for growth and structurally related to the recently reported peptidoglycan flippase of Escherichia coli, we speculate it performs an analogous function in S. aureus. These results suggest that SAV1754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.

The synthesis and reactions of 4-carbomethoxy β-sultams

Abstract The preparation of 4-carbomethoxy-1,2-thiazetidine-1,1-dioxides from carbomethoxymethanesulfonyl chloride and imines is described.

Magnetically manipulable polymeric supports for solid phase organic synthesis

Abstract The preparation of magnetite-impregnated polymeric supports for use in solid phase organic synthesis is described.

Nuclear analogs of β-lactam antibiotics II. The synthesis of 6α-(1-hydroxylethyl)-cyclonocardicins

Abstract The title compounds were synthesized in ten steps using as key ring-forming reactions an imine-acid chloride cyclization and a rhodium-mediated carbenoid insertion.

The preparation and alkylation of β-sultam mono- and dianions

Abstract The reaction of 2-unsubstituted 1,2-thiazetidine-1,1-dioxides with n-butyllithium affords dianions which react with a variety of electrophiles. Selective mono- and dialkylation is readily accomplished.