Undergraduate Honors Theses

Thesis Defended

Fall 2016

Document Type

Thesis

Type of Thesis

Departmental Honors

Department

Molecular, Cellular, & Developmental Biology

First Advisor

Corrella Detweiler

Second Advisor

Brian DeDecker

Third Advisor

Ricardo Stephen

Abstract

Although instances of antibiotic resistance are steadily rising, traditional screening platforms have stopped producing novel antibiotics. The combination of these two events has led to fear that we may enter a post-antibiotic era, where common infections will no longer be treatable. In order to combat this issue, Abigail Reens and Amy Crooks in our lab carried out a high-throughput screen that identifies compounds that prevent bacterial growth in mammalian cells instead of in laboratory media. They screened a library of 14,400 drug-like compounds for activity against Salmonella enterica growing within macrophages. Of 286 chemicals with antibacterial activity, I found that only five have antimicrobial activity in standard laboratory media. Conditions inside the host cell are vastly different than those in broth. In cells, bacterial survival depends on virulence genes, which are often dispensable in standard media. Our screen therefore has the potential to identify compounds that target virulence genes or that synergize with conditions in the host to have antibacterial activity. We have begun characterizing the activity of our top 56 structurally unrelated hits and have found diverse and exciting results. Three hits appear to have previously undescribed activity against bacterial efflux-pumps, demonstrating the power of our approach to identify new chemical scaffolds with antibiotic potential. The hits I studied include one that is a member of a family of antidepressants with known intracellular antibacterial activity, five compounds that synergize with antimicrobial peptides, and one with antibacterial activity that is potentiated by incubation with macrophage supernatant.

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