Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer

Cell Host & Microbe
Arnau DomenechJan-Willem Veening

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.

Citations

Aug 26, 2020·Journal of Bacteriology·Tiffany M Zarrella, Guangchun Bai
Mar 20, 2021·Nature Microbiology·Caroline A WerlangKatharina Ribbeck
Apr 10, 2020·Cell Host & Microbe·Jason W Rosch, Elaine I Tuomanen
Jun 8, 2021·Current Opinion in Microbiology·Jenifer MoralezAllison J Lopatkin
Aug 3, 2021·Peptide Science·Muralikrishna Lella, Yftah Tal-Gan

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