There is a critical need for novel therapeutics to treat antimicrobial-resistant Gram-negative bacteria. Historically, antibiotics were identified in screen using whole bacteria. Over the past 20 years, there has instead been intensive biochemical screening that targets bacterial molecules, an approach that has often identified compounds with significant barriers in either the pathogen or the mammalian host, including an inability to enter or remain within host or pathogen cells, destruction by the host or pathogen, or host cytotoxicity. We have therefore developed a quantitative, image-based high content screen that excludes compounds with undesirable properties because it uses whole, virulent, bacteria growing within mammalian cells. We propose to use this screen to identify therapeutics that target nonessential bacterial virulence factors and will be effective against antimicrobial-resistant bacteria.

Public Health Relevance

Across the globe, multi-drug resistant (MDR) bacterial strains cause significant morbidity and mortality; there is an urgent need for new antibiotics, including those that target conserved virulence determinants of Gram-negative pathogens. We propose a screen to identify such compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33AI121365-03
Application #
9591103
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Alexander, William A
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80303
Reens, Abigail L; Crooks, Amy L; Su, Chih-Chia et al. (2018) A cell-based infection assay identifies efflux pump modulators that reduce bacterial intracellular load. PLoS Pathog 14:e1007115