Open AccessRETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
Author(s) -
Kumar Sachin Singh,
Rolee Sharma,
Poli Adi Narayana Reddy,
Prashanthi Vonteddu,
Madeline Good,
Anjana Sundarrajan,
Hyeree Choi,
Kar Muthumani,
Andrew V. Kossenkov,
Aaron R. Goldman,
HsinYao Tang,
Maxim Totrov,
Joel Cassel,
Maureen E. Murphy,
Rajasekharan Somasundaram,
Meenhard Herlyn,
Joseph M. Salvino,
Farokh Dotiwala
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-03074-x
Subject(s) - microbiology and biotechnology , bacteria , biology , immune system , cytotoxic t cell , prodrug , yersinia , biochemistry , in vitro , immunology , genetics
Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration 1 . IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans 2,3 . Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations 4-6 . Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria-including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus-yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations.