Targeting the BspC-vimentin interaction to develop anti-virulence therapies during Group B streptococcal meningitis

Bacterial infections are a major cause of morbidity and mortality worldwide and the rise of antibiotic resistance necessitates development of alternative treatments. Pathogen adhesins that bind to host cells initiate disease pathogenesis and represent potential therapeutic targets. We have shown pre...

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Bibliographic Details
Published in:PLoS pathogens 2022-03, Vol.18 (3), p.e1010397
Main Authors: Manzer, Haider S, Villarreal, Ricardo I, Doran, Kelly S
Format: Article
Language:English
Subjects:
Adhesins
Adhesins, Bacterial - genetics
Adhesins, Bacterial - metabolism
Adhesion
Amino acids
Antibiotic resistance
Antibiotics
Bacterial diseases
Bacterial infections
Bacterial meningitis
Binding sites
Biology and Life Sciences
Brain
Care and treatment
Cellular proteins
Development and progression
Disease
Drug resistance
Drug screening
Endothelium
Genes
Genetic aspects
Genomes
Health aspects
Host-bacteria relationships
Humans
Infant, Newborn
Medicine and Health Sciences
Meningitis
Meningitis, Bacterial - metabolism
Morbidity
Mortality
Mutagenesis
Neonates
Pathogenesis
Pathogens
Phylogenetics
Protein binding
Proteins
Research and Analysis Methods
Site-directed mutagenesis
Streptococcal infections
Streptococcal Infections - microbiology
Streptococcus
Streptococcus agalactiae
Streptococcus infections
Therapeutic targets
Vimentin
Vimentin - metabolism
Virulence
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Summary:Bacterial infections are a major cause of morbidity and mortality worldwide and the rise of antibiotic resistance necessitates development of alternative treatments. Pathogen adhesins that bind to host cells initiate disease pathogenesis and represent potential therapeutic targets. We have shown previously that the BspC adhesin in Group B Streptococcus (GBS), the leading cause of bacterial neonatal meningitis, interacts with host vimentin to promote attachment to brain endothelium and disease development. Here we determined that the BspC variable (V-) domain contains the vimentin binding site and promotes GBS adherence to brain endothelium. Site directed mutagenesis identified a binding pocket necessary for GBS host cell interaction and development of meningitis. Using a virtual structure-based drug screen we identified compounds that targeted the V-domain binding pocket, which blocked GBS adherence and entry into the brain in vivo. These data indicate the utility of targeting the pathogen-host interface to develop anti-virulence therapeutics.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1010397