Host metabolites stimulate the bacterial proton motive force to enhance the activity of aminoglycoside antibiotics
0301 basic medicine
QH301-705.5
Immunology
Microbial Sensitivity Tests
Microbiology
03 medical and health sciences
Virology
Medicine and Health Sciences
Genetics
Humans
Pseudomonas Infections
Biology (General)
Molecular Biology
Lung
Cells, Cultured
Proton-Motive Force
Epithelial Cells
RC581-607
Anti-Bacterial Agents
3. Good health
Biofilms
Culture Media, Conditioned
Pseudomonas aeruginosa
Metabolome
Tobramycin
Parasitology
Immunologic diseases. Allergy
Research Article
DOI:
10.1371/journal.ppat.1007697
Publication Date:
2019-04-29T22:55:43Z
AUTHORS (11)
ABSTRACT
Antibiotic susceptibility of bacterial pathogens is typically evaluated using in vitro assays that do not consider the complex host microenvironment. This may help explaining a significant discrepancy between antibiotic efficacy and vivo, with some antibiotics being effective but vivo or vice versa. Nevertheless, it well-known bacteria driven by environmental factors. Lung epithelial cells enhance activity aminoglycoside against opportunistic pathogen Pseudomonas aeruginosa, yet mechanism behind unknown. The present study addresses this gap provides mechanistic understanding on how lung stimulate activity. To investigate influence local microenvironment activity, an vivo-like three-dimensional (3-D) cell model was used. We report conditioned medium 3-D cells, containing secreted cellular components, potentiated bactericidal aminoglycosides P. including resistant clinical isolates, several other pathogens. In contrast, obtained from same type, grown as conventional (2-D) monolayers did efficacy. found endogenous metabolites (including succinate glutamate) enhanced provide evidence pyruvate metabolism linked to observed potentiation antimicrobial Biochemical phenotypic indicated stimulated proton motive force (PMF), resulting increased intracellular pH. latter uptake, determined fluorescently labelled tobramycin combination flow cytometry analysis. Our findings reveal cross-talk metabolic pathways, downstream antibiotics. Understanding underlying basis lead improved diagnostic approaches pave way towards novel means
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