Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide

Stoessel, Daniel; Nowell, Cameron J.; Jones, Amy J.; Ferrins, Lori; Ellis, Katherine M.; Riley, Jennifer; Rahmani, Raphaël; Read, Kevin D.; McConville, Malcolm J.; Avery, Vicky M.; Baell, Jonathan B.; Creek, Darren J.

doi:10.1007/s11306-016-1062-1

Cited by 31 publications

(27 citation statements)

References 44 publications

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“…To avoid the loss of certain hydrophilic lipids (e.g., phospholipids), the single-phase Bligh-Dyer method was also performed in tandem. The performance of extraction solvents was assessed on the basis of the number and intensity of the peaks detected by reversed-phase liquid chromatography (RPLC) (27). Principal-component analysis (PCA) score plots were constructed to depict the impact of the solvent system used for extraction on the resultant lipidome, showing general differences among the three solvent systems ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa

Han

Zhu

Creek

et al. 2018

Antimicrob Agents Chemother

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Multidrug-resistant presents a global medical challenge, and polymyxins are a key last-resort therapeutic option. Unfortunately, polymyxin resistance in has been increasingly reported. The present study was designed to define metabolic differences between paired polymyxin-susceptible and -resistant strains using untargeted metabolomics and lipidomics analyses. The metabolomes of wild-type strain K ([PAK] polymyxin B MIC, 1 mg/liter) and its paired mutant strains, PAK and PAK (polymyxin B MICs of 16 mg/liter and 64 mg/liter, respectively) were characterized using liquid chromatography-mass spectrometry, and metabolic differences were identified through multivariate and univariate statistics. PAK and PAK, which displayed lipid A modifications with 4-amino-4-deoxy-l-arabinose, showed significant perturbations in amino acid and carbohydrate metabolism, particularly the intermediate metabolites from 4-amino-4-deoxy-l-arabinose synthesis and the methionine salvage cycle pathways. The genomics result showed a premature termination (Y275stop) in (encoding spermidine synthase) in PAK, and metabolomics data revealed a decreased intracellular level of spermidine in PAK compared to that in PAK Our results indicate that spermidine may play an important role in high-level polymyxin resistance in Interestingly, both mutants had decreased levels of phospholipids, fatty acids, and acyl-coenzyme A compared to those in the wild-type PAK. Moreover, the more resistant PAK mutant exhibited much lower levels of phospholipids than the PAK mutant, suggesting that the decreased phospholipid level was associated with polymyxin resistance. In summary, this study provides novel mechanistic information on polymyxin resistance in and highlights its impacts on bacterial metabolism.

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Section: Resultsmentioning

confidence: 99%

Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa

Han

Zhu

Creek

et al. 2018

Antimicrob Agents Chemother

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“…MMV688372 was identified through the development of an oxazolopyridine series and was shown to possess potent activity against T. brucei brucei , with an example from this series demonstrating efficacy in a mouse model of trypanosomiasis ( 86 ). A separate study also found representatives from the related oxazol-2-ylanilide to be active against T. brucei brucei ( 33 ), and in a metabolomics study an analogue was discovered to target sphingolipid metabolism in T. brucei brucei ( 87 ). In addition, a structurally related azabenzoxazole has recently been identified as a proteasome inhibitor in all three kinetoplastid parasites as a part of the Novartis Research Foundation Genomics Institute kinetoplastid screening campaign ( 88 ).…”

Section: Discussionmentioning

confidence: 99%

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery

Duffy

Sykes

Jones

et al. 2017

Antimicrob Agents Chemother

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115

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Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro. Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research.

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“…Three biological replicates were prepared for each cell line and treatment. Samples were analysed by hydrophilic interaction liquid chromatography coupled to high resolution-mass spectrometry (LC-MS) according to a previously published method (Stoessel et al, 2016). All samples were analyzed as a single batch, in randomized order and pooled quality control samples were analyzed regularly throughout the batch to confirm reproducibility.…”

Section: Methodsmentioning

confidence: 99%

Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate

Counihan

Chisholm

Bullen

et al. 2017

eLife

135

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Plasmodium falciparum parasites, the causative agents of malaria, modify their host erythrocyte to render them permeable to supplementary nutrient uptake from the plasma and for removal of toxic waste. Here we investigate the contribution of the rhoptry protein RhopH2, in the formation of new permeability pathways (NPPs) in Plasmodium-infected erythrocytes. We show RhopH2 interacts with RhopH1, RhopH3, the erythrocyte cytoskeleton and exported proteins involved in host cell remodeling. Knockdown of RhopH2 expression in cycle one leads to a depletion of essential vitamins and cofactors and decreased de novo synthesis of pyrimidines in cycle two. There is also a significant impact on parasite growth, replication and transition into cycle three. The uptake of solutes that use NPPs to enter erythrocytes is also reduced upon RhopH2 knockdown. These findings provide direct genetic support for the contribution of the RhopH complex in NPP activity and highlight the importance of NPPs to parasite survival.DOI: http://dx.doi.org/10.7554/eLife.23217.001

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Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide

Cited by 31 publications

References 44 publications

Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa

Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery

Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate

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