Summary of Study ST003024

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001879. The data can be accessed directly via it's Project DOI: 10.21228/M8TX45 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003024
Study TitleIdentifying and mathematically modeling the time-course of extracellular metabolic markers associated with resistance to ceftolozane/tazobactam in Pseudomonas aeruginosa - Part 1
Study TypeBiomedical research
Study SummaryExtracellular bacterial metabolites have potential as markers of bacterial growth and resistance emergence, but have not been evaluated in dynamic in vitro studies. We investigated the dynamic metabolomic footprint of a multidrug-resistant hypermutable Pseudomonas aeruginosa isolate exposed to ceftolozane/tazobactam as continuous infusion (4.5g/day, 9g/day) in a hollow-fiber infection model over 7-9 days in biological replicates (n=5). Bacterial samples were collected at 0, 7, 23, 47, 71, 95, 143, 167, 191 and 215h, the supernatant quenched and extracellular metabolites extracted. Metabolites were analyzed via untargeted metabolomics, including hierarchical clustering and correlation with quantified total and resistant bacterial populations. The time-courses of five metabolites were mathematically modeled. These five (of 1921 detected) metabolites were from enriched pathways (arginine and central carbon metabolism). Absorbed L-arginine and secreted L-ornithine were highly correlated with the total bacterial population (r -0.79 and 0.82 respectively, p<0.0001). Ribose-5-phosphate, sedoheptulose-7-phosphate and trehalose-6-phosphate correlated with the resistant subpopulation (0.64, 0.64 and 0.67, respectively, p<0.0001), and were likely secreted due to resistant growth overcoming oxidative and osmotic stress induced by ceftolozane/tazobactam. Using PK/PD-based transduction models, these metabolites were successfully modeled based on the total or resistant bacterial populations. The models well described the abundance of each metabolite across the differing time-course profiles of biological replicates, based on bacterial killing and, importantly, resistant regrowth. These proof-of-concept studies suggest further exploration is warranted to determine the generalizability of these findings. The metabolites modeled in this work are not exclusive to bacterial cells. Future studies may use this approach to identify bacteria-specific metabolites correlating with resistance, which would ultimately be extremely useful for clinical translation.
Institute
Monash Institute of Pharmaceutical Sciences
DepartmentMonash Institute of Pharmaceutical Sciences
LaboratoryCornelia Landersdorfer
Last NameLandersdorfer
First NameCornelia
Address399 Royal Pd
Emaildovile.anderson@monash.edu
Phone0448671141
Submit Date2023-12-17
Num Groups6 groups with time points
Total SubjectsNA
Num MalesNA
Num FemalesNA
PublicationsIdentifying and mathematically modeling the time-course of extracellular metabolic markers associated with resistance to ceftolozane/tazobactam in Pseudomonas aeruginosa
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2024-01-11
Release Version1
Cornelia Landersdorfer Cornelia Landersdorfer
https://dx.doi.org/10.21228/M8TX45
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Treatment:

Treatment ID:TR003147
Treatment Summary:Ceftolozane-tazobactam was administered to simulate steady-state concentrations of ceftolozane predicted to occur in the epithelial lining fluid of the lung in patients with CF, following daily doses of 3 g/1.5 g and 6 g/3 g via continuous infusion (10.6 and 21.3 mg/L, respectively) (21-23). Total bacterial populations were quantified on antibiotic-free CAMHA, and resistant subpopulations on CAMHA containing ceftolozane-tazobactam (12 and 20 mg/L).
Treatment:continuous infusion
Treatment Compound:Ceftolozane-tazobactam
Treatment Dose:3 g and 6 g
Treatment Dosevolume:10.6 and 21.3 mg/L
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