Exploring the Mechanism of Action of Lipophilic Small Molecule Anti-Infectives

Undergraduate Honors Thesis

Citations

Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/2f75r945c

Abstract

The antimicrobial resistance crisis threatens global health, and the lack of novel antibiotics discovered since the 1970s is partly to blame. Resistant Gram-negative bacteria are especially difficult to treat due to their posession of an outer membrane, which excludes from the cell many small molecules with antimicrobial activity. Here, I report the identification of three related small molecules, collectively called “Class 1,” which have bacteriostatic and bactericidal activity against Gram-negative bacteria under conditions that disturb the outer membrane. In agreement with their high lipophilicities, these compounds appear to target the inner membrane. This work investigates the nature of these compounds’ interaction with the inner membrane through biochemical measures of membrane voltage and barrier function. Additionally, I attempt to further advance our understanding of these compounds’ mechanisms of action through generation of resistant mutants, a screen of a CRISPRi essential gene library, and comparison with other compounds that also appear to target the bacterial inner membrane.

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