Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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 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.

SUBMITTER: Singh KS

PROVIDER: S-EPMC8776033 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Dual-acting IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance

Project description:Isoprenoids are vital to all organisms in supporting core functions of life, like respiration and membrane stability. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential to gram-negative bacteria, mycobacteria and apicomplexans. The IspH substrate, HMBPP, is not produced in humans and other metazoans and activates cytotoxic T-cells in humans and primates at extremely low concentrations. 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 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 T-cells, thus inhibiting the rise of antibiotic resistant bacterial populations.

2020-10-22 | MSV000086359 | MassIVE

Bacteria can mobilize nematode-trapping fungi to kill nematodes.

Project description:In their natural habitat, bacteria are consumed by bacterivorous nematodes; however, they are not simply passive preys. Here we report a defensive mechanism used by certain bacteria to mobilize nematode-trapping fungi to kill nematodes. These bacteria release urea, which triggers a lifestyle switch in the fungus Arthrobotrys oligospora from saprophytic to nematode-predatory form; this predacious form is characterized by formation of specialized cellular structures or 'traps'. The bacteria significantly promote the elimination of nematodes by A. oligospora. Disruption of genes involved in urea transport and metabolism in A. oligospora abolishes the urea-induced trap formation. Furthermore, the urea metabolite ammonia functions as a signal molecule in the fungus to initiate the lifestyle switch to form trap structures. Our findings highlight the importance of multiple predator-prey interactions in prey defense mechanisms.

| S-EPMC4275587 | biostudies-literature

Membrane-active macromolecules kill antibiotic-tolerant bacteria and potentiate antibiotics towards Gram-negative bacteria.

Project description:Chronic bacterial biofilms place a massive burden on healthcare due to the presence of antibiotic-tolerant dormant bacteria. Some of the conventional antibiotics such as erythromycin, vancomycin, linezolid, rifampicin etc. are inherently ineffective against Gram-negative bacteria, particularly in their biofilms. Here, we report membrane-active macromolecules that kill slow dividing stationary-phase and antibiotic tolerant cells of Gram-negative bacteria. More importantly, these molecules potentiate antibiotics (erythromycin and rifampicin) to biofilms of Gram-negative bacteria. These molecules eliminate planktonic bacteria that are liberated after dispersion of biofilms (dispersed cells). The membrane-active mechanism of these molecules forms the key for potentiating the established antibiotics. Further, we demonstrate that the combination of macromolecules and antibiotics significantly reduces bacterial burden in mouse burn and surgical wound infection models caused by Acinetobacter baumannii and Carbapenemase producing Klebsiella pneumoniae (KPC) clinical isolate respectively. Colistin, a well-known antibiotic targeting the lipopolysaccharide (LPS) of Gram-negative bacteria fails to kill antibiotic tolerant cells and dispersed cells (from biofilms) and bacteria develop resistance to it. On the contrary, these macromolecules prevent or delay the development of bacterial resistance to known antibiotics. Our findings emphasize the potential of targeting the bacterial membrane in antibiotic potentiation for disruption of biofilms and suggest a promising strategy towards developing therapies for topical treatment of Gram-negative infections.

| S-EPMC5570306 | biostudies-literature

Exploiting phage receptor binding proteins to enable endolysins to kill Gram-negative bacteria.

Project description:Bacteriophage-encoded endolysins degrading the bacterial peptidoglycan are promising antibacterials for combating antibiotic-resistant bacteria. However, endolysins have limited use against Gram-negative bacteria, since the outer membrane prevents access to the peptidoglycan. Here, we present Innolysins, an innovative concept for engineering endolysins to exert antibacterial activity against Gram-negative bacteria. Innolysins combine the enzymatic activity of endolysins with the binding capacity of phage receptor binding proteins (RBPs). As proof-of-concept, we constructed 12 Innolysins by fusing phage T5 endolysin and RBP Pb5 in different configurations. One of these, Innolysin Ec6 displayed antibacterial activity against Escherichia coli only in the presence of Pb5 receptor FhuA, leading to 1.22 ± 0.12 log reduction in cell counts. Accordingly, other bacterial species carrying FhuA homologs such as Shigella sonnei and Pseudomonas aeruginosa were sensitive to Innolysin Ec6. To enhance the antibacterial activity, we further constructed 228 novel Innolysins by fusing 23 endolysins with Pb5. High-throughput screening allowed to select Innolysin Ec21 as the best antibacterial candidate, leading to 2.20 ± 0.09 log reduction in E. coli counts. Interestingly, Innolysin Ec21 also displayed bactericidal activity against E. coli resistant to third-generation cephalosporins, reaching a 3.31 ± 0.53 log reduction in cell counts. Overall, the Innolysin approach expands previous endolysin-engineering strategies, allowing customization of endolysins by exploiting phage RBPs to specifically target Gram-negative bacteria.

| S-EPMC7374709 | biostudies-literature

Time-kill activity of the streptogramin NXL 103 against Gram-positive and -negative bacteria.

Project description:Against 33 Gram-positive and -negative bacteria, NXL 103 MICs were 0.03 to 1 ?g/ml. NXL 103 was bactericidal by 12 h at 2 × MIC against all 5 pneumococci and at 2 × MIC after 24 h against all 5 group A and B ?-hemolytic streptococci. NXL 103 was bactericidal against all 8 Haemophilus influenzae strains at 2 × MIC and all 5 Moraxella catarrhalis strains at 4 × MIC after 24 h but was mainly bacteriostatic against 5 methicillin-resistant Staphylococcus aureus strains. After the exposure of one strain of each species to NXL 103 for 10 daily subcultures, the MICs remained within ± 1 dilution.

| S-EPMC3067140 | biostudies-literature

Gram negative bacteria

Project description:Gram negative bacteria Genome sequencing

| PRJNA594823 | ENA

Gram-negative bacteria

Project description:This deposit is composed of paired-end reads from 90 isolates of four different gram-negative bacterial species. The raw reads were used to generate predictions of antimicrobial resistance. Raw sequence reads

| PRJNA388450 | ENA

Gram Negative Bacteria

Project description:Escherichia coli, Klebsiella oxytoca, Pseudomonas putida Raw sequence reads

| PRJNA668381 | ENA

gram-negative bacteria

Project description:Escherichia coli & Klebsiella pneumoniae raw sequence reads

| PRJNA306133 | ENA

Gram negative bacteria

Project description:Antimicrobial susceptibility and integron diversity in organic and conventionally grown fruits and vegetables

| PRJNA311932 | ENA