Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics

Arnaud Gutierrez; Saloni Jain; Prerna Bhargava; Meagan Hamblin; Michael A Lobritz; James J Collins

doi:10.1016/j.molcel.2017.11.012

Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics

Mol Cell. 2017 Dec 21;68(6):1147-1154.e3. doi: 10.1016/j.molcel.2017.11.012. Epub 2017 Dec 7.

Authors

Arnaud Gutierrez¹, Saloni Jain², Prerna Bhargava¹, Meagan Hamblin³, Michael A Lobritz⁴, James J Collins⁵

Affiliations

¹ Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
² Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02115, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁴ Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 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: 29225037
DOI: 10.1016/j.molcel.2017.11.012

Abstract

Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for this persistence is unclear. Here, we show that exhaustion of the metabolic inputs that couple carbon catabolism to oxidative phosphorylation is a primary cause of growth phase-dependent persistence to quinolone antibiotics. Supplementation of stationary-phase cultures with glucose and a suitable terminal electron acceptor to stimulate respiratory metabolism is sufficient to sensitize cells to quinolone killing. Using this approach, we successfully sensitize high-density populations of Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis to quinolone antibiotics. Our findings link growth-dependent quinolone persistence to discrete impairments in respiratory metabolism and identify a strategy to kill non-dividing bacteria.

Keywords: antibiotic; drug persistence; oxidative phosphorylation; quinolones.

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 / growth & development
Bacterial Infections / drug therapy*
Bacterial Infections / microbiology
Carbon / metabolism*
Cell Respiration / physiology*
Drug Resistance, Bacterial*
Microbial Sensitivity Tests
Oxidative Phosphorylation
Oxygen / metabolism*
Quinolones / pharmacology*

Substances

Anti-Bacterial Agents
Quinolones
Carbon
Oxygen