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  • 1
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    Generation of quinolone antimalarials [Pharmacology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-05-23
    Description: There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc1. Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Single cell activity reveals direct electron transfer in methanotrophic consortia (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-17
    Description: Multicellular assemblages of microorganisms are ubiquitous in nature, and the proximity afforded by aggregation is thought to permit intercellular metabolic coupling that can accommodate otherwise unfavourable reactions. Consortia of methane-oxidizing archaea and sulphate-reducing bacteria are a well-known environmental example of microbial co-aggregation; however, the coupling mechanisms between these paired organisms is not well understood, despite the attention given them because of the global significance of anaerobic methane oxidation. Here we examined the influence of interspecies spatial positioning as it relates to biosynthetic activity within structurally diverse uncultured methane-oxidizing consortia by measuring stable isotope incorporation for individual archaeal and bacterial cells to constrain their potential metabolic interactions. In contrast to conventional models of syntrophy based on the passage of molecular intermediates, cellular activities were found to be independent of both species intermixing and distance between syntrophic partners within consortia. A generalized model of electric conductivity between co-associated archaea and bacteria best fit the empirical data. Combined with the detection of large multi-haem cytochromes in the genomes of methanotrophic archaea and the demonstration of redox-dependent staining of the matrix between cells in consortia, these results provide evidence for syntrophic coupling through direct electron transfer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGlynn, Shawn E -- Chadwick, Grayson L -- Kempes, Christopher P -- Orphan, Victoria J -- England -- Nature. 2015 Oct 22;526(7574):531-5. doi: 10.1038/nature15512. Epub 2015 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, California 91125, USA. ; Exobiology Branch, National Aeronautics and Space Administration Ames Research Center, Moffett Field, California 94035, USA. ; Control and Dynamical Systems, California Institute of Technology, Pasadena, California 91125, USA. ; SETI Institute, Mountain View, California 94034, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26375009" target="_blank"〉PubMed〈/a〉
    Keywords: Anaerobiosis ; Archaea/cytology/*metabolism ; Cytochromes/genetics/metabolism/ultrastructure ; Deltaproteobacteria/cytology/*metabolism ; Diffusion ; Electron Transport ; Genome, Archaeal/genetics ; Genome, Bacterial/genetics ; Heme/metabolism ; Methane/*metabolism ; Microbiota/physiology ; Models, Biological ; Molecular Sequence Data ; *Single-Cell Analysis ; Sulfates/metabolism ; *Symbiosis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Methane metabolism in the archaeal phylum Bathyarchaeota revealed by genome-centric metagenomics (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-24
    Description: Methanogenic and methanotrophic archaea play important roles in the global flux of methane. Culture-independent approaches are providing deeper insight into the diversity and evolution of methane-metabolizing microorganisms, but, until now, no compelling evidence has existed for methane metabolism in archaea outside the phylum Euryarchaeota. We performed metagenomic sequencing of a deep aquifer, recovering two near-complete genomes belonging to the archaeal phylum Bathyarchaeota (formerly known as the Miscellaneous Crenarchaeotal Group). These genomes contain divergent homologs of the genes necessary for methane metabolism, including those that encode the methyl-coenzyme M reductase (MCR) complex. Additional non-euryarchaeotal MCR-encoding genes identified in a range of environments suggest that unrecognized archaeal lineages may also contribute to global methane cycling. These findings indicate that methane metabolism arose before the last common ancestor of the Euryarchaeota and Bathyarchaeota.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Evans, Paul N -- Parks, Donovan H -- Chadwick, Grayson L -- Robbins, Steven J -- Orphan, Victoria J -- Golding, Suzanne D -- Tyson, Gene W -- New York, N.Y. -- Science. 2015 Oct 23;350(6259):434-8. doi: 10.1126/science.aac7745.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia 4072, Queensland, Australia. ; Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125, USA. ; School of Earth Sciences, University of Queensland, St Lucia 4072, Queensland, Australia. ; Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia 4072, Queensland, Australia. Advanced Water Management Centre, University of Queensland, St Lucia 4072, Queensland, Australia. g.tyson@uq.edu.au.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26494757" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Artificial electron acceptors decouple archaeal methane oxidation from sulfate reduction (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: The oxidation of methane with sulfate is an important microbial metabolism in the global carbon cycle. In marine methane seeps, this process is mediated by consortia of anaerobic methanotrophic archaea (ANME) that live in syntrophy with sulfate-reducing bacteria (SRB). The underlying interdependencies within this uncultured symbiotic partnership are poorly understood. We used a combination of rate measurements and single-cell stable isotope probing to demonstrate that ANME in deep-sea sediments can be catabolically and anabolically decoupled from their syntrophic SRB partners using soluble artificial oxidants. The ANME still sustain high rates of methane oxidation in the absence of sulfate as the terminal oxidant, lending support to the hypothesis that interspecies extracellular electron transfer is the syntrophic mechanism for the anaerobic oxidation of methane.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scheller, Silvan -- Yu, Hang -- Chadwick, Grayson L -- McGlynn, Shawn E -- Orphan, Victoria J -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):703-7. doi: 10.1126/science.aad7154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912857" target="_blank"〉PubMed〈/a〉
    Keywords: Anaerobiosis ; *Carbon Cycle ; Electron Transport ; Geologic Sediments/microbiology ; Methane/*metabolism ; Methanosarcinales/classification/genetics/*metabolism ; Molecular Sequence Data ; Oxidation-Reduction ; Phylogeny ; RNA, Archaeal/classification/genetics ; Seawater/microbiology ; Sulfates/*metabolism ; Sulfur-Reducing Bacteria/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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