The oral microbiome represents an extremely diverse environment that harbors many species of bacteria; over 700 different species have been identified overall. These organisms may be either commensal or pathogenic, and reside in multi-species communities of bacterial biofilms. As such, these bacteria may be 100-1000 times less susceptible to antibiotic treatment than their planktonic counterparts. One pathogenic organism that exists as a biofilm in the oral cavity is Streptococcus mutans, the main etiologic agent contributing to dental caries. Recently, the myxobacterial natural product carolacton was isolated and shown to be lethal to S. mutans cells in a biofilm at low (10 nM) concentration. As part of an endeavor to take inspiration from natural products to develop new therapeutics to combat biofilms, our group became interested in carolacton. This dissertation describes research conducted into the synthesis and biological evaluation of carolacton. Total synthesis enabled the biological evaluation of carolacton as well as several analogs. A novel compound was identified that was shown to elicit a phenotypic response from S. mutans that was different from that elicited by carolacton. In an effort to uncover novel simplified carolacton derivatives that maintain bioactivity and/or act via a different mechanism, we have exploited the power of diverted total synthesis in order to obtain a 1st-generation library of carolacton analogs. By leveraging a common intermediate that we were then able to diversify, we have obtained a library of simplified aryl analogs. Preliminary testing of these analogs has revealed a compound that inhibits growth and formation of S. mutans biofilms. This research has enabled us to obtain compounds that will serve to guide future drug discovery efforts, as well as act as tool compounds to help identify novel drug targets in S. mutans biofilms. / Chemistry
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/875 |
| Date | January 2016 |
| Creators | Brzozowski, Richard Stephen |
| Contributors | Wuest, William M., Andrade, Rodrigo B., Minbiole, Kevin P. C., Sieburth, Scott McNeill |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 276 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/857, Theses and Dissertations |
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