Back to Search
Start Over
IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.
- Source :
-
Nature [Nature] 2021 Jan; Vol. 589 (7843), pp. 597-602. Date of Electronic Publication: 2020 Dec 23. - Publication Year :
- 2021
-
Abstract
- Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration <superscript>1</superscript> . IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans <superscript>2,3</superscript> . 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 <superscript>4-6</superscript> . 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.
- Subjects :
- Animals
Drug Resistance, Microbial
Drug Resistance, Multiple
Enzyme Inhibitors chemistry
Escherichia coli Proteins genetics
Escherichia coli Proteins metabolism
Female
Half-Life
Humans
Leukocytes, Mononuclear drug effects
Leukocytes, Mononuclear immunology
Leukocytes, Mononuclear microbiology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microbial Sensitivity Tests
Molecular Docking Simulation
Oxidoreductases deficiency
Oxidoreductases genetics
Oxidoreductases metabolism
Prodrugs pharmacokinetics
Prodrugs pharmacology
Substrate Specificity
Swine blood
T-Lymphocytes, Cytotoxic immunology
Drug Design
Enzyme Inhibitors pharmacology
Escherichia coli Proteins antagonists & inhibitors
Gram-Negative Bacteria drug effects
Gram-Negative Bacteria immunology
Lymphocyte Activation drug effects
Microbial Viability drug effects
Oxidoreductases antagonists & inhibitors
T-Lymphocytes, Cytotoxic drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 589
- Issue :
- 7843
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 33361818
- Full Text :
- https://doi.org/10.1038/s41586-020-03074-x