IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.

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 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 mul

SUBMITTER: Singh KS 

PROVIDER: S-EPMC8776033 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature