Summary of Study ST002747

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 PR001710. The data can be accessed directly via it's Project DOI: 10.21228/M8P43M 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 IDST002747
Study TitleEvolutionary genomics identifies host-directed therapeutics to treat intracellular bacterial infections
Study SummaryObligate intracellular bacteria from the Rickettsiaceae family have shed essential biosynthetic pathways during their evolution towards host dependency. By systematically comparing this cytosolic family of bacteria to the related vacuolar Anaplasmataceae family using a novel computational pipeline called PoMeLo, we identified 20 metabolic pathways that may have been lost since the divergence of Anaplasmataceae and Rickettsiaceae, corresponding to the latter’s change to a cytosolic niche. We hypothesized that drug inhibition of these host metabolic pathways would reduce the levels of metabolic products available to the bacteria, thereby inhibiting bacterial growth. We tested 22 commercially available inhibitors for 14 of the identified pathways and found that 59% of the inhibitors reduced bacterial growth at concentrations that did not contribute to host cell cytotoxicity. Of these, 5 inhibitors with an IC50 under 5 µM were tested to determine whether their mode of inhibition was bactericidal or bacteriostatic. Both mycophenolate mofetil, an inhibitor of inosine-5'-monophosphate dehydrogenase in the purine biosynthesis pathway, and roseoflavin, an analog of riboflavin, displayed bactericidal activity. We then took an unbiased metabolomics approach to Rickettsia-infected cells to determine whether there was any overlap between our predicted host pathways and depletion of metabolite levels in infected cells, as measured by mass spectrometry. Our results show that 13 pathways were identified as metabolic gaps in both our computational predictions and our metabolomics analysis. These in vitro validation studies support the feasibility of a novel evolutionary genomics-guided approach for antibiotic drug development against obligate pathogens.
Institute
CZ Biohub
Last NameDeFelice
First NameBrian
Address1291 Welch Rd., Rm. G0821 (SIM1), Stanford CA, California, 94305, USA
Emailbcdefelice@ucdavis.edu
Phone5303564485
Submit Date2023-06-23
Raw Data AvailableYes
Raw Data File Type(s)mzML, raw(Thermo)
Analysis Type DetailLC-MS
Release Date2023-07-07
Release Version1
Brian DeFelice Brian DeFelice
https://dx.doi.org/10.21228/M8P43M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Cultured cells; Subject species: Rickettsia parkeri; Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Treatment
SA289292VIAH002_BK_3_Pos_QE1_Lipids_030blank blank
SA289293VIAH002_BK_1_Neg_QE1_Lipids_007blank blank
SA289294VIAH002_BK_3_Neg_QE1_Lipids_031blank blank
SA289295VIAH002_BK_2_Pos_QE1_Lipids_018blank blank
SA289296VIAH002_BK_2_Neg_QE1_Lipids_019blank blank
SA289297VIAH002H_BK_2_Pos_QE2_HILIC_018blank blank
SA289298VIAH002H_BK_3_Pos_QE2_HILIC_030blank blank
SA289299VIAH002H_BK_1_Pos_QE2_HILIC_006blank blank
SA289300VIAH002H_BK_1_Neg_QE2_HILIC_007blank blank
SA289301VIAH002H_BK_2_Neg_QE2_HILIC_019blank blank
SA289302VIAH002H_BK_3_Neg_QE2_HILIC_031blank blank
SA289303VIAH002_BK_1_Pos_QE1_Lipids_006blank blank
SA289252M5_uninfected_NA_5__012Human control
SA289253M5_uninfected_NA_5__013Human control
SA289254M1_uninfected_NA_1__017Human control
SA289255VIAH002H_Pos_M1_QE2_HILIC_008Human control
SA289256M3_uninfected_NA_3__011Human control
SA289257VIAH002H_Pos_M4_QE2_HILIC_028Human control
SA289258M2_uninfected_NA_2__009Human control
SA289259M2_uninfected_NA_2__008Human control
SA289260VIAH002H_Neg_M4_QE2_HILIC_029Human control
SA289261VIAH002H_Neg_M3_QE2_HILIC_021Human control
SA289262VIAH002H_Pos_M3_QE2_HILIC_020Human control
SA289263M4_uninfected_NA_4__029Human control
SA289264VIAH002H_Neg_M2_QE2_HILIC_011Human control
SA289265VIAH002H_Pos_M2_QE2_HILIC_010Human control
SA289266VIAH002H_Neg_M1_QE2_HILIC_009Human control
SA289267VIAH002H_Pos_M5_QE2_HILIC_014Human control
SA289268VIAH002H_Neg_M5_QE2_HILIC_015Human control
SA289269M3_uninfected_NA_3__010Human control
SA289270M1_uninfected_NA_1__016Human control
SA289271M4_uninfected_NA_4__028Human control
SA289272Inf2_infected_NA_2__020Rickettsia parkeri & human PostInfection
SA289273Inf1_infected_NA_1__024Rickettsia parkeri & human PostInfection
SA289274Inf3_infected_NA_3__026Rickettsia parkeri & human PostInfection
SA289275Inf3_infected_NA_3__027Rickettsia parkeri & human PostInfection
SA289276Inf1_infected_NA_1__025Rickettsia parkeri & human PostInfection
SA289277Inf4_infected_NA_4__023Rickettsia parkeri & human PostInfection
SA289278Inf4_infected_NA_4__022Rickettsia parkeri & human PostInfection
SA289279Inf2_infected_NA_2__021Rickettsia parkeri & human PostInfection
SA289280Inf5_infected_NA_5__014Rickettsia parkeri & human PostInfection
SA289281VIAH002H_Pos_Inf3_QE2_HILIC_016Rickettsia parkeri & human PostInfection
SA289282VIAH002H_Neg_Inf5_QE2_HILIC_013Rickettsia parkeri & human PostInfection
SA289283VIAH002H_Pos_Inf5_QE2_HILIC_012Rickettsia parkeri & human PostInfection
SA289284Inf5_infected_NA_5__015Rickettsia parkeri & human PostInfection
SA289285VIAH002H_Pos_Inf1_QE2_HILIC_022Rickettsia parkeri & human PostInfection
SA289286VIAH002H_Neg_Inf3_QE2_HILIC_017Rickettsia parkeri & human PostInfection
SA289287VIAH002H_Neg_Inf1_QE2_HILIC_023Rickettsia parkeri & human PostInfection
SA289288VIAH002H_Neg_Inf2_QE2_HILIC_027Rickettsia parkeri & human PostInfection
SA289289VIAH002H_Neg_Inf4_QE2_HILIC_025Rickettsia parkeri & human PostInfection
SA289290VIAH002H_Pos_Inf2_QE2_HILIC_026Rickettsia parkeri & human PostInfection
SA289291VIAH002H_Pos_Inf4_QE2_HILIC_024Rickettsia parkeri & human PostInfection
Showing results 1 to 52 of 52
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