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Genome-wide antibiotic-CRISPRi profiling identifies LiaR activation as a strategy to resensitize fluoroquinolone-resistant Streptococcus pneumoniae
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Genome-wide antibiotic-CRISPRi profiling identifies LiaR activation as a strategy to resensitize fluoroquinolone-resistant Streptococcus pneumoniae
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Journal Article
Genome-wide antibiotic-CRISPRi profiling identifies LiaR activation as a strategy to resensitize fluoroquinolone-resistant Streptococcus pneumoniae
2025
Overview
Streptococcus pneumoniae
is a human pathogen that has become increasingly resistant to synthetic fluoroquinolone antibiotics that target bacterial topoisomerases. To identify pathways essential under fluoroquinolone stress and potential novel targets to revitalize use of this antibiotic class, we perform genome-wide CRISPRi-seq screens and generate antibiotic-gene essentiality signatures. Expectedly, genes involved in DNA recombination and repair become more important under fluoroquinolone-induced DNA damage, including
recA
,
recJ
,
recF
,
recO
,
rexAB
, and
ruvAB
. Surprisingly, specific downregulation of the gene encoding the histidine kinase LiaS caused fluoroquinolone hypersensitivity. LiaS is part of the LiaFSR (VraTSR) three-component regulatory system involved in cell envelope homeostasis. We show that LiaS keeps the response regulator LiaR inactive, and that
liaS
deletion causes LiaR hyperphosphorylation and upregulation of the LiaR regulon. We use RNA-seq to refine the LiaR regulon, highlighting the role of heat-shock response and pleiotropic regulator SpxA2 in fluoroquinolone sensitivity. Activating the LiaR-regulon by the cell envelope-targeting antibiotic bacitracin synergized with ciprofloxacin and levofloxacin, restoring sensitivity in fluoroquinolone-resistant strains in vitro. Furthermore, bacitracin/levofloxacin combination therapy is effective in vivo and improved treatment of fluoroquinolone-resistant
S. pneumoniae
infection in a zebrafish meningitis model. These findings offer a starting point for identification and validation of potent combination therapies to treat antibiotic-resistant pneumococcal infections.
Streptococcus pneumoniae, the causative agent of pneumococcal disease, has become increasingly resistant to fluoroquinolones. Through CRISPRi-seq, the authors identify the role of the LiaFSR operon in resensitizing S. pneumoniae to fluoroquinolones.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/23
/ 38/39
/ 45/47
/ 64/116
/ Animals
/ Anti-Bacterial Agents - pharmacology
/ Bacteria
/ Bacterial Proteins - genetics
/ Bacterial Proteins - metabolism
/ Ciprofloxacin - pharmacology
/ DNA
/ Drug Resistance, Bacterial - drug effects
/ Drug Resistance, Bacterial - genetics
/ Fluoroquinolones - pharmacology
/ Gene Expression Regulation, Bacterial - drug effects
/ Genes
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mutation
/ Pneumococcal Infections - drug therapy
/ Pneumococcal Infections - microbiology
/ Science
/ Streptococcus pneumoniae - drug effects
/ Streptococcus pneumoniae - genetics
