RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance

Kumar Sachin Singh, Rishabh Sharma, Poli Adi Narayana Reddy, Prashanthi Vonteddu, Madeline Good, Anjana Sundarrajan, Hyeree Choi, Kar Muthumani, Andrew Kossenkov, Aaron R. Goldman, Hsin-Yao Tang, Maxim Totrov, Joel Cassel, Maureen E. Murphy, Rajasekharan Somasundaram, Meenhard Herlyn, Joseph M. Salvino () and Farokh Dotiwala ()
Additional contact information
Kumar Sachin Singh: The Wistar Institute
Rishabh Sharma: The Wistar Institute
Poli Adi Narayana Reddy: The Wistar Institute
Prashanthi Vonteddu: The Wistar Institute
Madeline Good: The Wistar Institute
Anjana Sundarrajan: The Wistar Institute
Hyeree Choi: The Wistar Institute
Kar Muthumani: The Wistar Institute
Andrew Kossenkov: The Wistar Institute
Aaron R. Goldman: The Wistar Institute
Hsin-Yao Tang: The Wistar Institute
Maxim Totrov: Molsoft
Joel Cassel: The Wistar Institute
Maureen E. Murphy: The Wistar Institute
Rajasekharan Somasundaram: The Wistar Institute
Meenhard Herlyn: The Wistar Institute
Joseph M. Salvino: The Wistar Institute
Farokh Dotiwala: The Wistar Institute

Nature, 2021, vol. 589, issue 7843, 597-602

Abstract: Abstract Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. 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 concentrations4–6. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03074-x

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