RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance

Abstract

Isoprenoids are vital to all organisms in supporting core functions of life, like respiration and membrane stability. 1 IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential to gram-negative bacteria, mycobacteria and apicomplexans. 2 , 3 The IspH substrate, HMBPP, is not produced in humans and other metazoans and activates cytotoxic Vγ9Vδ2 T-cells in humans and primates at extremely low concentrations. 4 - 6 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 Vγ9Vδ2 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 γδ T-cells, which may limit the rise of antibiotic resistant bacterial populations.

Biomimetic nanomedicine-triggered in situ vaccination for innate and adaptive immunity activations for bacterial osteomyelitis treatment

“…2f). 7 All the above results suggest that HMMP is capable of disrupting the integrity of bacteria and consequently promote the outward release of bacterial antigens. In the meantime, we analyzed the intrabacterial ROS generation performance to disclose the underlying antibacterial mechanism induced by HMMP.…”

“…4,5 However, a crucial drawback of these methods is the limited depth of light penetration, making them impotent in eliminating deep bone infections. 6 The emergence and circulation of multidrug-resistant strains, such as Staphylococcus aureus (S. aureus) and Mycobacterium tuberculosis (M. tuberculosis), are largely attributed to their capability to mount effective anti-immune responses 7,8 . Invading pathogens could inhibit antigen presentations by camou aging their antigen epitopes to escape from immune surveillance, reprogramming macrophages to an M2 phenotype and/or even killing antigen-presenting cells.…”

Gut Microbiome and Drug Metabolism

“…Другим следствием из взаимосвязи генетических особенностей микробиоты и реакции организма хозяина на лечение является еще один подход к поиску терапии: влияние на экспрессию тех или иных генов у конкретных бактерий. Singh и соавторы показали [8] [10].…”

Predicting drug targets by homology modelling of Pseudomonas aeruginosa proteins of unknown function

“…[2–4] Generally, the most attractive targets for new classes of antibiotics are proteins involved in previously untargeted essential biochemical pathways conserved among pathogens and absent in humans. [1, 5] Targeted screening of such enzymes identified reductase IspH involved in isoprenoid biosynthesis [6], reductase FabI involved in fatty acid biosynthesis [7] and peptidase LspA involved in posttranslational processing of lipoprotein [8] which respective inhibition by C23.28–TPP (pre-clinical study) [6], isoniazid (approved drug) [7] and myxovirescin (clinical phase 3) [8] showed strong antibacterial activity.…”