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
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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