Summary of project PR001710

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, 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.


Project ID: PR001710
Project DOI:doi: 10.21228/M8P43M
Project Title:Evolutionary genomics identifies host-directed therapeutics to treat intracellular bacterial infections
Project Summary:Obligate 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 Name:DeFelice
First Name:Brian
Address:1291 Welch Rd., Rm. G0821 (SIM1), Stanford CA, California, 94305, USA

Summary of all studies in project PR001710

Study IDStudy TitleSpeciesInstituteAnalysis
(* : Contains Untargted data)
(* : Contains raw data)
ST002747 Evolutionary genomics identifies host-directed therapeutics to treat intracellular bacterial infections Rickettsia parkeri; Homo sapiens CZ Biohub MS 2023-07-07 1 52 Uploaded data (2.3G)*