Eradicating Bacterial Persisters with Combinations of Strongly and Weakly Metabolism-Dependent Antibiotics

Erica J Zheng; Jonathan M Stokes; James J Collins

doi:10.1016/j.chembiol.2020.08.015

Eradicating Bacterial Persisters with Combinations of Strongly and Weakly Metabolism-Dependent Antibiotics

Cell Chem Biol. 2020 Dec 17;27(12):1544-1552.e3. doi: 10.1016/j.chembiol.2020.08.015. Epub 2020 Sep 10.

Authors

Erica J Zheng¹, Jonathan M Stokes², James J Collins³

Affiliations

¹ Program in Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Machine Learning for Pharmaceutical Discovery and Synthesis Consortium, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: stokesjm@mit.edu.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA. Electronic address: jimjc@mit.edu.

PMID: 32916087
DOI: 10.1016/j.chembiol.2020.08.015

Abstract

The vast majority of bactericidal antibiotics display poor efficacy against bacterial persisters, cells that are in a metabolically repressed state. Molecules that retain their bactericidal functions against such bacteria often display toxicity to human cells, which limits treatment options for infections caused by persisters. Here, we leverage insight into metabolism-dependent bactericidal antibiotic efficacy to design antibiotic combinations that sterilize both metabolically active and persister cells, while minimizing the antibiotic concentrations required. These rationally designed antibiotic combinations have the potential to improve treatments for chronic and recurrent infections.

Keywords: antibiotic combinations; antibiotics; bacterial persisters; metabolism.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Anti-Bacterial Agents / pharmacology*
Bacteria / drug effects*
Bacteria / metabolism*
Biofilms / drug effects
Drug Design
Drug Interactions
Drug Resistance, Bacterial / drug effects
Microbial Sensitivity Tests

Substances

Anti-Bacterial Agents