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

Autor:	Zimmerman SM; Department of Infectious Diseases University of Georgia College of Veterinary Medicine, Athens, Georgia, USA., Lafontaine AJ; Department of Infectious Diseases University of Georgia College of Veterinary Medicine, Athens, Georgia, USA., Herrera CM; Department of Infectious Diseases University of Georgia College of Veterinary Medicine, Athens, Georgia, USA., Mclean AB; Department of Infectious Diseases University of Georgia College of Veterinary Medicine, Athens, Georgia, USA., Trent MS; Department of Infectious Diseases University of Georgia College of Veterinary Medicine, Athens, Georgia, USA strent@uga.edu.; Center of Vaccines and Immunology, University of Georgia College of Veterinary Medicine, Athens, Georgia, USA.; Department of Microbiology, College of Arts and Sciences, University of Georgia, Athens, Georgia, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2020 Feb 21; Vol. 64 (3). Date of Electronic Publication: 2020 Feb 21 (Print Publication: 2020).
DOI:	10.1128/AAC.01677-19
Abstrakt:	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 ( E nterococcus faecium , S taphylococcus aureus , K lebsiella pneumoniae , A cinetobacter baumannii , P seudomonas aeruginosa , and E nterobacter 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 Escherichia coli 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 <2 μg/ml against polymyxin-resistant and polymyxin-heteroresistant Gram-negative pathogens. Likewise, four of these compounds exhibit antimicrobial activity against Gram-positive bacteria, one of which rapidly eradicated methicillin-resistant Staphylococcus aureus We present multiple first-generation (i.e., not yet optimized) compounds that warrant further investigation and optimization, since they can act both synergistically with polymyxin and also as lone antimicrobials for combating ESKAPE pathogens. (Copyright © 2020 American Society for Microbiology.)
Databáze:	MEDLINE
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