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Please use this identifier to cite or link to this item: http://arks.princeton.edu/ark:/88435/dsp01h702q929q
Title: A PIPELINE FOR CHARACTERIZING NOVEL MECHANISMS OF ACTION IDENTIFIES A DUAL-TARGETING ANTIBIOTIC
Authors: Martin II, James Keith
Advisors: Gitai, Zemer
Contributors: Molecular Biology Department
Keywords: Antibiotic Resistance
Antibiotics
Anti-cancer
Bacterial Pathogens
Broad Spectrum
Dual Mechanism of action
Subjects: Biology
Issue Date: 2019
Publisher: Princeton, NJ : Princeton University
Abstract: The rise of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. In an animal host model, SCH-79797 reduces pathogenesis of Acinetobacter baumannii, a drug-resistant Gram-negative pathogen. To characterize the MoA of SCH-79797 we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline shows that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments with other antifolates and membrane disruptors in killing MRSA persisters. Thus, SCH-79797 represents a promising lead antibiotic and suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to target challenging bacterial pathogens.
URI: http://arks.princeton.edu/ark:/88435/dsp01h702q929q
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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