Graduation Year

2020

Date of Submission

5-2020

Document Type

Open Access Senior Thesis

Degree Name

Bachelor of Arts

Department

Chemistry

Reader 1

Professor Ethan Van Arnam

Reader 2

Professor Amy Babbes

Terms of Use & License Information

Terms of Use for work posted in Scholarship@Claremont.

Abstract

Tirandamycin is a small molecule natural product that has been isolated from various species of marine and terrestrial Streptomyces. The natural product has shown antibacterial activity against an array of Gram-positive and Gram-negative bacteria, showing promise as a pharmaceutical drug. Tirandamycin has 14 known derivatives, many of which have been created synthetically. Some of its derivatives are particularly potent against the high-risk bacteria vancomycin-resistant Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae and Escherichia coli. However, the antibacterial potency of these derivatives has not been tested systematically leading to the possibility of discovering more potent derivatives of the drug which could combat the rise of multi-drug resistant forms of these bacteria. Additionally, understanding tirandamycin’s structural basis of inhibition would allow for future manipulation of tirandamycin’s base structure to maximize antibacterial potency. While it is known that tirandamycin targets bacterial RNAp, there is still a need to determine where tirandamycin specifically binds to the enzyme, including the interactions between its amino acid residues and tirandamycin. A screening of the derivatives of tirandamycin against these high-risk bacteria is proposed to discover possibly potent but currently untested derivatives of tirandamycin. Additionally, x-ray crystallography of the tirandamycin-RNAp complex and site-directed mutagenesis of E. coli RNAp is proposed to determine the structural basis of inhibition by tirandamycin.

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