Year of Award
Doctor of Philosophy (PhD)
Department or School/College
Department of Chemistry and Biochemistry
Nigel D. Priestley, Brooke Martin, Holly Thompson, Michele McGuirl
antibiotics, library synthesis, methicillin-resistant Staphylococcus aureus, natural product, nonactin, triazoles
University of Montana
Since Alexander Fleming first noted the killing of a bacterial culture by a mold, antibiotics have revolutionized medicine, being able to treat, and often cure life-threatening illnesses and making surgical procedures possible by eliminating the possibility of opportunistic infection. However, during the past 30 years many of the infections that were once easily cured by the proper antibiotic are no longer so due to a precipitous rise in multi-drug resistant organisms. This rise in multi-drug resistant organisms poses a grave threat to the medical advances that have been made in the past century and underscores the need for new antibiotics. We have developed two promising candidates for pharmaceutical applications, compounds 72 and 71, which are derived from nonactin, a biologically active natural product. Nonactin 40, an ionophore macrotetrolide antibiotic that is produced by Streptomyces griseus ETH A7796, is an ideal candidate for the synthesis of new antimicrobial drugs. This secondary metabolite is composed of two units of (+)-nonactic acid 49 and two units of (-)-nonactic acid 50. Whereas nonactin does not possess a synthetically useful chemical `handle', the nonactic acid subunits do. Through methanolysis of this structure and the separation of the two enantiomers, followed by a series of transformations, easily diversifiable scaffolds have been synthesized, which allows for the relatively rapid synthesis of chemically diverse libraries. From a small library of compounds that were synthesized, the compounds, 72 and 71 were found to show promising activities against vancomycin-resistant Enterococcus faecalis (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Compounds 88 and 90 were shown to be the active enantiomers. It was also shown by making the 1,4-substituted triazoles and the 1,5-substituted triazoles 91, 92 that only the 1,4-substituted triazoles gave the aforementioned activities. These results illustrate the vital importance of stereochemistry and regiochemistry. To establish the importance of the nonactic acid moiety itself in the triazoloester compounds, analogues of these compounds were made by replacing the nonactic acid moiety with a cyclohexane moiety, specifically starting with both trans and cis 4-cyclohexanol-carboxylic acid. Neither the cis nor the trans analogues 131, 132, 142, 143, 151, 152, 160, 161 of either of the regioisomers of the compounds made to mimic 72 and 71 gave the activities of their nonactate-containing counterparts. As an alternative to chemical synthesis we investigated biotransformation of nonactic acid analogs by Streptomyces griseus. While we were unable to generate new nonactin analogues we did discover an inhibitor of nonactin biosynthesis 186 and we were able to set limits on precursor directed biosynthesis in S. griseus.
Phillips, Joshua Bryant, "The Use of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities" (2010). Graduate Student Theses, Dissertations, & Professional Papers. 1100.
© Copyright 2010 Joshua Bryant Phillips