MassIVE MSV000086359

Partial Public PXD022136

Dual-acting IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance

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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. [doi:10.25345/C5J205] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: proteomics ; isoprenoid synthesis

Contact

Principal Investigators:
(in alphabetical order) 		Farokh Dotiwala, The Wistar Institute, United States
Submitting User: tangh

Publications

Singh KS, Sharma R, Reddy PAN, Vonteddu P, Good M, Sundarrajan A, Choi H, Muthumani K, Kossenkov A, Goldman AR, Tang HY, Totrov M, Cassel J, Murphy ME, Somasundaram R, Herlyn M, Salvino JM, Dotiwala F.
IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.
Nature. Epub 2020 Dec 23.

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