PXD022136-1
PXD022136 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Dual-acting IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance |
| Description | Isoprenoids are vital to all organisms in supporting core functions of life, like respiration and membrane stability. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential to gram-negative bacteria, mycobacteria and apicomplexans. The IspH substrate, HMBPP, is not produced in humans and other metazoans and activates cytotoxic T-cells in humans and primates at extremely low concentrations. We describe novel IspH inhibitors and through structure-guided analog design, refine their potency to nanomolar levels. We have modified these into prodrugs for delivery into bacteria and report that they kill clinical isolates of several multidrug resistant bacterial species such as Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus, while being relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with prodrugs resemble those with conditional IspH knockdown. Notably, these prodrugs also cause expansion and activation of human T-cells in a humanized mouse model of bacterial infection. These IspH prodrugs synergize direct antibiotic killing with a simultaneous rapid immune response by cytotoxic T-cells, thus inhibiting the rise of antibiotic resistant bacterial populations. |
| HostingRepository | MassIVE |
| AnnounceDate | 2020-10-22 |
| AnnouncementXML | Submission_2020-10-22_12:10:05.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Hsin-Yao Tang |
| SpeciesList | scientific name: Escherichia coli; common name: E. coli; NCBI TaxID: 562; |
| ModificationList | Oxidation; Carbamidomethyl |
| Instrument | Q Exactive HF |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2020-10-22 11:17:05 | ID requested | |
| ⏵ 1 | 2020-10-22 12:10:05 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: proteomics, isoprenoid synthesis |
Contact List
| Farokh Dotiwala | |
|---|---|
| contact affiliation | The Wistar Institute |
| contact email | fdotiwala@wistar.org |
| lab head | |
| Hsin-Yao Tang | |
| contact affiliation | The Wistar Institute |
| contact email | tangh@wistar.org |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/MSV000086359/ |
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