Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer

Arnau Domenech; Ana Rita Brochado; Vicky Sender; Karina Hentrich; Birgitta Henriques-Normark; Athanasios Typas; Jan-Willem Veening

doi:10.1016/j.chom.2020.02.002

Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer

Cell Host Microbe. 2020 Apr 8;27(4):544-555.e3. doi: 10.1016/j.chom.2020.02.002. Epub 2020 Mar 3.

Authors

Arnau Domenech¹, Ana Rita Brochado², Vicky Sender³, Karina Hentrich³, Birgitta Henriques-Normark⁴, Athanasios Typas², Jan-Willem Veening⁵

Affiliations

¹ Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, Centre for Synthetic Biology, University of Groningen, Groningen 9747AG, the Netherlands; Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Biophore Building, Lausanne 1015, Switzerland.
² European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
³ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
⁴ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Clinical Microbiology, Karolinska University Hospital Solna, Stockholm 171 76, Sweden.
⁵ Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, Centre for Synthetic Biology, University of Groningen, Groningen 9747AG, the Netherlands; Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Biophore Building, Lausanne 1015, Switzerland. Electronic address: [email protected].

PMID: 32130952
DOI: 10.1016/j.chom.2020.02.002

Abstract

Streptococcus pneumoniae is a commensal of the human nasopharynx that can also cause severe antibiotic-resistant infections. Antibiotics drive the spread of resistance by inducing S. pneumoniae competence, in which bacteria express the transformation machinery that facilitates uptake of exogenous DNA and horizontal gene transfer (HGT). We performed a high-throughput screen and identified potent inhibitors of S. pneumoniae competence, called COM-blockers. COM-blockers limit competence by inhibiting the proton motive force (PMF), thereby disrupting export of a quorum-sensing peptide that regulates the transformation machinery. Known chemical PMF disruptors and alterations in pH homeostasis similarly inhibit competence. COM-blockers limit transformation of clinical multi-drug-resistant strains and HGT in infected mice. At their active concentrations, COM-blockers do not affect growth, compromise antibiotic activity, or elicit detectable resistance. COM-blockers provide an experimental tool to inhibit competence and other PMF-involved processes and could help reduce the spread of virulence factors and antibiotic resistance in bacteria. VIDEO ABSTRACT.

Keywords: DNA uptake; Streptococcus pneumoniae; antibiotic resistance; competence development; horizontal gene transfer; transformation.

Publication types

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

MeSH terms

Animals
Anti-Bacterial Agents / adverse effects
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / drug effects
Drug Resistance, Microbial / drug effects
Drug Resistance, Multiple / drug effects
Gene Transfer, Horizontal* / drug effects
Humans
Mice
Proton-Motive Force*
Quorum Sensing / drug effects
Streptococcus pneumoniae* / drug effects
Streptococcus pneumoniae* / metabolism
Virulence Factors

Substances

Anti-Bacterial Agents
Bacterial Proteins
Virulence Factors
competence factor, Streptococcus

Abstract

Publication types

MeSH terms

Substances

Grants and funding