A Whole-Cell Screen Identifies Small Bioactives That Synergize with Polymyxin and Exhibit Antimicrobial Activities against Multidrug-Resistant Bacteria

The threat of diminished antibiotic discovery has global health care in crisis. In the United States, it is estimated each year that over 2 million bacterial infections are resistant to first-line antibiotic treatments and cost in excess of 20 billion dollars. Many of these cases result from infecti...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2020-02, Vol.64 (3)
Main Authors: Zimmerman, Shawn M, Lafontaine, Audrey-Ann J, Herrera, Carmen M, Mclean, Amanda B, Trent, M Stephen
Format: Article
Language:English
Subjects:
Acinetobacter baumannii - drug effects
Anti-Bacterial Agents - pharmacology
Colistin - pharmacology
Drug Resistance, Multiple, Bacterial - drug effects
Enterococcus faecium - drug effects
Escherichia coli - drug effects
Gram-Negative Bacteria - drug effects
Gram-Positive Bacteria - drug effects
Klebsiella pneumoniae - drug effects
Microbial Sensitivity Tests
Polymyxin B - pharmacology
Polymyxins - pharmacology
Pseudomonas aeruginosa - drug effects
Staphylococcus aureus - drug effects
Susceptibility
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Summary:The threat of diminished antibiotic discovery has global health care in crisis. In the United States, it is estimated each year that over 2 million bacterial infections are resistant to first-line antibiotic treatments and cost in excess of 20 billion dollars. Many of these cases result from infection with the ESKAPE pathogens ( , , , , , and species), which are multidrug-resistant bacteria that often cause community- and hospital-acquired infections in both healthy and immunocompromised patients. Physicians have turned to last-resort antibiotics like polymyxins to tackle these pathogens, and as a consequence, polymyxin resistance has emerged and is spreading. Barring the discovery of new antibiotics, another route to successfully mitigate polymyxin resistance is to identify compounds that can complement the existing arsenal of antibiotics. We recently designed and performed a large-scale robotic screen to identify 43 bioactive compounds that act synergistically with polymyxin B to inhibit the growth of polymyxin-resistant Of these 43 compounds, 5 lead compounds were identified and characterized using various Gram-negative bacterial organisms to better assess their synergistic activity with polymyxin. Several of these compounds reduce polymyxin to an MIC of
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.01677-19