New molecules to combat the bacterial antibiotic resistance problem
Sintim, Herman O
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Platensimycin/platencin are recently discovered natural products that inhibit membrane formation in bacteria and cyclic diguanylic acid (c-di-GMP) is a master regulator of bacterial biofilm formation. The rise of bacterial antibiotic resistance and the dwindling pipeline of new antibiotics make these molecules of interest to the scientific community. This dissertation reports the design, synthesis and biological evaluation of analogs of platensimycin/platencin and c-di-GMP. Platensimycin and platencin have garnered interest from synthetic chemists due to the complexity of their molecular architecture, coupled with their exciting biological profile (inhibition of bacterial fatty acid synthases). We have developed a concise synthetic approach towards the platensimycin/platencin class of antibiotics. The highlight of our synthesis is the use of dynamic ring-closing metathesis to prepare a bicyclo intermediate and a tandem nucleophilic addition of organolithium to a ketone moiety, followed by a subsequent ring opening of a nearby epoxide to generate complex tricyclic framework. The synthesis of platensimycin or closely related analogs requires multi-steps (average of 17 overall steps). Using a function-oriented synthetic approach, we developed short syntheses of N,N-dialkyl benzoic acid derivatives of platensimycin, and we demonstrate that these readily prepared molecules have comparable antibiotic properties to the difficult-to-synthesize platensimycin/platencin. C-di-GMP has been dubbed the master regulator of bacterial "lifestyle" due to the key role that this molecule plays in bacterial biofilm formation and virulence formation. In order to study c-di-GMP signaling in bacteria, with the ultimate goal of using key insights gained from such studies to develop anti-biofilm or anti-virulence agents, we prepared analogs of c-di-GMP and studied their biophysical and biological profiles. Interestingly, we reveal that conservative modifications to c-di-GMP affect both the biophysical and biochemical properties of this molecule. We also demonstrate a concept called "conformational steering" as a powerful principle to selectively target different classes of receptor proteins that bind to c-di-GMP.