Angiotensin II Receptor Type 1—A Novel Target for Preventing Neonatal Meningitis in Mice by Escherichia coli K1

The increasing incidence of Escherichia coli K1 meningitis due to escalating antibiotic resistance warrants alternate treatment options to prevent this deadly disease. We screened a library of small molecules from the National Institutes of Health clinical collection and identified telmisartan, an a...

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Bibliographic Details
Published in:The Journal of infectious diseases 2014-02, Vol.209 (3), p.409-419
Main Authors: Krishnan, Subramanian, Shanmuganathan, Muthusamy V., Behenna, Douglas, Stoltz, Brian M., Prasadarao, Nemani V.
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Antigens, Bacterial
Bacteria
Bacterial Capsules
Bacteriology
Benzimidazoles - pharmacology
Benzimidazoles - therapeutic use
Benzoates - pharmacology
Benzoates - therapeutic use
Biological and medical sciences
Cell Line
Chemoprevention - methods
Cytometry
Disease Models, Animal
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - microbiology
Escherichia coli
Escherichia coli - chemistry
Escherichia coli - classification
Escherichia coli - physiology
Escherichia coli meningitis
Fundamental and applied biological sciences. Psychology
Humans
Infections
Infectious diseases
Major and Brief Reports
Medical sciences
Meningitis, Escherichia coli - prevention & control
Mice
Mice, Inbred C57BL
Microbiology
Miscellaneous
Molecules
Phosphorylation
Polysaccharides, Bacterial
Receptor, Angiotensin, Type 1 - metabolism
Receptors
Small interfering RNA
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Summary:The increasing incidence of Escherichia coli K1 meningitis due to escalating antibiotic resistance warrants alternate treatment options to prevent this deadly disease. We screened a library of small molecules from the National Institutes of Health clinical collection and identified telmisartan, an angiotensin II receptor type 1 (ATIR) blocker, as a potent inhibitor of E. coli invasion into human brain microvascular endothelial cells (HBMECs). Immunoprecipitation studies revealed that ATIR associates with endothelial cell gp96, the receptor in HBMECs for E. coli outer membrane protein A. HBMECs pretreated with telmisartan or transfected with ATIR small interfering RNA were resistant to E. coli invasion because of downregulation of protein kinase C-α phosphorylation. Administration of a soluble derivative of telmisartan to newborn mice before infection with E. coli prevented the onset of meningitis and suppressed neutrophil infiltration and glial cell migration in the brain. Therefore, telmisartan has potential as an alternate treatment option for preventing E. coli meningitis.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jit499