Jon Clardy

Harvard Medical School, Boston, Massachusetts, United States

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Publications (722)4241 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Bromide and chloride analogs of the commonly used zinc iodide-based metal organic framework for the crystalline sponge method were synthesized and evaluated. Inclusion of (1R)-(–)-menthyl acetate into these MOFs was analysed using third-generation synchrotron radiation, and the effects and potential benefits of varying the MOF terminal ligand are discussed.
    Chemical Communications 06/2015; Accepted. DOI:10.1039/C5CC03840E · 6.72 Impact Factor
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    ABSTRACT: Two novel 4,8,8-trimethylcyclooct-2-enone derivatives, chakyunglupulins A and B, together with six known lignans were isolated from the aerial part of Barleria lupulina. The structures of new compounds were established by extensive spectroscopic data and HR-MS, and their absolute configurations were determined by a combination of NOE experiment and application of the modified Mosher’s method.
    Tetrahedron Letters 05/2015; 56(21). DOI:10.1016/j.tetlet.2015.04.023 · 2.39 Impact Factor
  • Science translational medicine 05/2015; 7(288):288ra77-288ra77. DOI:10.1126/scitranslmed.aaa3575 · 14.41 Impact Factor
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    ABSTRACT: A new octaketide, named cytosporone V (1), and two other known phenylethanoid glycosides (2-3), were isolated from the aerial parts of Pogostemon cablin (Blanco) Benth. The structure of 1 was elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR and HR-MS. Compounds 1-3 displayed weak antibacterial activity against two gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus. All isolates were also evaluated for their antiproliferative activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15). Compounds 2 and 3 showed significant cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with IC50 values ranging from 2.73 to 9.52μM. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry letters 05/2015; 25(14). DOI:10.1016/j.bmcl.2015.04.094 · 2.33 Impact Factor
  • Alexandra M Cantley, Jon Clardy
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    ABSTRACT: This Viewpoint article provides a brief and selective summary of research on the chemical ecology underlying symbioses between bacteria and animals. Animals engage in multiple highly specialized interactions with bacteria that reflect their long coevolutionary history. The article focuses on a few illustrative but hardly exhaustive examples in which bacterially produced small molecules initiate a developmental step with important implications for the evolution of animals, provide signals for the maturation of mammalian immune systems, and furnish chemical defenses against microbial pathogens.
    Natural Product Reports 02/2015; DOI:10.1039/c4np00141a · 10.72 Impact Factor
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    ABSTRACT: Phytochemical investigation of an extract of the aerial part of Barleria lupulina resulted in the identification of four new iridoid glycosides (1-4), together with 14 known analogues (5-18). The structures of 1-4 were determined through 1D and 2D NMR spectroscopic data analysis, HRMS, and acid hydrolysis. This is the first report of iridoid glycosides with a formate group. The free-radical scavenging activity of compounds 9, 12, and 15-17 was assessed using the DPPH assay. Compounds 16 and 17 scavenged DPPH radicals weakly with IC50 values of 97.5 and 78.6 μg/mL, respectively.
    Journal of Natural Products 01/2015; 80(10). DOI:10.1021/np500791a · 3.95 Impact Factor
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    ABSTRACT: A detailed set of synthetic and crystallographic guidelines for the crystalline sponge method based upon the analysis of expediently synthesized crystal sponges using third-generation synchrotron radiation are reported. The procedure for the synthesis of the zinc-based metal-organic framework used in initial crystal sponge reports has been modified to yield competent crystals in 3 days instead of 2 weeks. These crystal sponges were tested on some small molecules, with two being unexpectedly difficult cases for analysis with in-house diffractometers in regard to data quality and proper space-group determination. These issues were easily resolved by the use of synchrotron radiation using data-collection times of less than an hour. One of these guests induced a single-crystal-to-single-crystal transformation to create a larger unit cell with over 500 non-H atoms in the asymmetric unit. This led to a non-trivial refinement scenario that afforded the best Flack x absolute stereochemical determination parameter to date for these systems. The structures did not require the use of PLATON/SQUEEZE or other solvent-masking programs, and are the highest-quality crystalline sponge systems reported to date where the results are strongly supported by the data. A set of guidelines for the entire crystallographic process were developed through these studies. In particular, the refinement guidelines include strategies to refine the host framework, locate guests and determine occupancies, discussion of the proper use of geometric and anisotropic displacement parameter restraints and constraints, and whether to perform solvent squeezing/masking. The single-crystal-to-single-crystal transformation process for the crystal sponges is also discussed. The presented general guidelines will be invaluable for researchers interested in using the crystalline sponge method at in-house diffraction or synchrotron facilities, will facilitate the collection and analysis of reliable high-quality data, and will allow construction of chemically and physically sensible models for guest structural determination.
    01/2015; A71:46–58. DOI:10.1107/S2053273314019573
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    ABSTRACT: A new naphthalenone, (R)-4,6,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone and a new isocoumarin, 6,8-dihydroxy-(3R)-(2-oxopropyl)-3,4-dihydroisocoumarin, together with eight related known compounds were isolated from the endolichenic fungal species, CR1546C from Costa Rican lichen Sticta fuliginosa (Lobariaceae). Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques and chemical methods. All of the isolated compounds exhibited moderate antifungal activity against the yeast Candida albicans.
    Journal of Chemical Research 12/2014; 38(23). DOI:10.3184/174751914X14175406270662 · 0.70 Impact Factor
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    ABSTRACT: We report a preliminary functional and complete structural characterization of a highly unusual geldanamycin analog, natalamycin A, that was isolated from Streptomyces strain M56 recovered from a South African nest of Macrotermes natalensis termites. Bioassay-guided fractionation based on antifungal activity led to the isolation of natalamycin A, and a combination of NMR spectroscopy and X-ray crystallographic analysis, including highly-accurate quantum-chemical NMR calculations on the largest and most conformationally-flexible system to date, revealed natalamycin A's three-dimensional solid- and solution-state structure. This structure along with the structures of related compounds isolated from the same source suggest a geldanamycin-like biosynthetic pathway with unusual post-PKS modifications.
    Chemical Science 11/2014; 5(11):-. DOI:10.1039/C4SC01136H · 8.60 Impact Factor
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    ABSTRACT: Roseobacticides regulate the symbiotic relationship between a marine bacterium (Phaeobacter inhibens) and a marine microalga (Emiliania huxleyi). This relationship can be mutualistic, when the algal host provides food for the bacteria and the bacteria produce growth hormones and antibiotics for the algae, or parasitic, when the algae senesce and release p-coumaric acid. The released p-coumaric acid causes the bacteria to synthesize roseobacticides, which are nM-μM toxins for the algae. We examined the biosynthesis of roseobacticides and report that all roseobacticide precursors play critical roles during the mutualist phase of the symbiosis. Roseobacticides are biosynthesized from the algal growth promoter, the major food molecule provided by the algal cells, and the algal senescence signal that initiates the mutualist-to-parasite switch. Thus, molecules that are beneficial during mutualism are diverted to the synthesis of toxins during parasitism. A plausible mechanism for assembling roseobacticides from these molecules is proposed.
    Journal of the American Chemical Society 10/2014; 136(43). DOI:10.1021/ja508782y · 11.44 Impact Factor
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    ABSTRACT: Dictyonema huaorani, a new species represented by a well-developed specimen found in the Ecuadorian Amazon region, is described in this paper. The material was collected during a Harvard ethnobotanical expedition in 1981 and originally determined by Mason E. Hale Jr. as belonging in the genus Dictyonema (D. sericeum s. lat.) and possibly representing an undescribed species. The species is morphologically distinctive in forming densely woven, semicircular thalli, closely resembling those of the paleotropical D. ligulatum but lacking clamps and with hyphal sheath around the photobiont filaments that resembles those of Cyphellostereum species. The species was reported to have hallucinogenic properties and chemical analyses suggest certain substances present that are shared with the hallucinogenic mushroom Psilocybe cubensis. Due to our inability to use pure reference compounds and scarce amount of sample for compound identification, however, our analyses were not able to determine conclusively the presence of hallucinogenic substances.
    The Bryologist 10/2014; 117(4):386-394. DOI:10.1639/0007-2745-117.4.386 · 0.73 Impact Factor
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    ABSTRACT: In complex biological systems, small molecules often mediate microbe-microbe and microbe-host interactions. Using a systematic approach, we identified 3,118 small-molecule biosynthetic gene clusters (BGCs) in genomes of human-associated bacteria and studied their representation in 752 metagenomic samples from the NIH Human Microbiome Project. Remarkably, we discovered that BGCs for a class of antibiotics in clinical trials, thiopeptides, are widely distributed in genomes and metagenomes of the human microbiota. We purified and solved the structure of a thiopeptide antibiotic, lactocillin, from a prominent member of the vaginal microbiota. We demonstrate that lactocillin has potent antibacterial activity against a range of Gram-positive vaginal pathogens, and we show that lactocillin and other thiopeptide BGCs are expressed in vivo by analyzing human metatranscriptomic sequencing data. Our findings illustrate the widespread distribution of small-molecule-encoding BGCs in the human microbiome, and they demonstrate the bacterial production of drug-like molecules in humans. PAPERCLIP:
    Cell 09/2014; 158(6):1402-14. DOI:10.1016/j.cell.2014.08.032 · 33.12 Impact Factor
  • ChemBioChem 09/2014; 15(13):1841-1841. DOI:10.1002/cbic.201490045 · 3.06 Impact Factor
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    ABSTRACT: Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small-molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood-stage malaria. Most of the screening hits inhibited both liver- and blood-stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin-dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide-3-kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual-stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development.
    ChemBioChem 09/2014; 15(13). DOI:10.1002/cbic.201400025 · 3.06 Impact Factor
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    ABSTRACT: Biochemical high-throughput screening is widely used in drug discovery, using a variety of small molecule libraries. However, broader screening strategies may be more beneficial to identify novel biological mechanisms. In the current study we utilized a β-galactosidase complementation method to screen a selection of microbial-derived pre-fractionated natural product extracts for those that increase Regulator of G protein Signaling 2 (RGS2) protein levels. RGS2 is a member of a large family of proteins that all regulate signaling through G protein-coupled receptors (GPCRs) by accelerating GTPase activity on active Gα as well as through other mechanisms. RGS2(-/-) mice are hypertensive, show increased anxiety and are prone to heart failure. RGS2 has a very short protein half-life due to rapid proteasomal degradation and we propose that enhancement of RGS2 protein levels could be a beneficial therapeutic strategy. Bioassay-guided fractionation of one of the hit strains yielded a pure compound, Indolactam V, a known protein kinase C (PKC) activator, which selectively increased RGS2 protein levels in a time- and concentration-dependent manner. Similar results were obtained with phorbol 12-myristate 13-acetate (PMA) as well as activation of the Gq-coupled muscarinic M3 receptor. The effect on RGS2 protein levels was blocked by the non-selective PKC inhibitor Go6983, the PKCβ-selective inhibitor Ruboxastaurin, as well as siRNA-mediated knockdown of PKCβ. Indolactam V-mediated increases in RGS2 protein levels also had functional effects on GPCR signaling. This study provides important proof-of-concept for our screening strategy and could define a negative feedback mechanism in Gq/PLC signaling through RGS2 protein up-regulation.
    Molecular pharmacology 08/2014; 86(4). DOI:10.1124/mol.114.092403 · 4.12 Impact Factor
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    ABSTRACT: Although biosynthetic gene clusters (BGCs) have been discovered for hundreds of bacterial metabolites, our knowledge of their diversity remains limited. Here, we used a novel algorithm to systematically identify BGCs in the extensive extant microbial sequencing data. Network analysis of the predicted BGCs revealed large gene cluster families, the vast majority uncharacterized. We experimentally characterized the most prominent family, consisting of two subfamilies of hundreds of BGCs distributed throughout the Proteobacteria; their products are aryl polyenes, lipids with an aryl head group conjugated to a polyene tail. We identified a distant relationship to a third subfamily of aryl polyene BGCs, and together the three subfamilies represent the largest known family of biosynthetic gene clusters, with more than 1,000 members. Although these clusters are widely divergent in sequence, their small molecule products are remarkably conserved, indicating for the first time the important roles these compounds play in Gram-negative cell biology.
    Cell 07/2014; 158(2):412-21. DOI:10.1016/j.cell.2014.06.034 · 33.12 Impact Factor
  • Planta Medica 07/2014; 80(10). DOI:10.1055/s-0034-1382403 · 2.34 Impact Factor
  • Planta Medica 07/2014; 80(10). DOI:10.1055/s-0034-1382404 · 2.34 Impact Factor
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    ABSTRACT: Studies on the origin of animal multicellularity have increasingly focused on one of the closest living relatives of animals, the choanoflagellate Salpingoeca rosetta. Single cells of S. rosetta can develop into multicellular rosette-shaped colonies through a process of incomplete cytokinesis. Unexpectedly, the initiation of rosette development requires bacterially produced small molecules. Previously, our laboratories reported the planar structure and femtomolar rosette-inducing activity of one rosette-inducing small molecule, dubbed rosette-inducing factor 1 (RIF-1), produced by the Gram-negative Bacteroidetes bacterium Algoriphagus machipongonensis. RIF-1 belongs to the small and poorly explored class of sulfonolipids. Here, we report a modular total synthesis of RIF-1 stereoisomers and structural analogs. Rosette-induction assays using synthetic RIF 1 stereoisomers and naturally occurring analogs defined the absolute stereochemistry of RIF-1 and revealed a remarkably restrictive set of structural requirements for inducing rosette development.
    Journal of the American Chemical Society 07/2014; 136(29). DOI:10.1021/ja5046692 · 11.44 Impact Factor
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    ABSTRACT: Actinobacteria in the genus Streptomyces are critical players in microbial communities that decompose complex carbohydrates in the soil, and these bacteria have recently been implicated in the deconstruction of plant polysaccharides for some herbivorous insects. Despite the importance of Streptomyces to carbon cycling, the extent of their plant biomass degrading ability remain largely unknown. Here, we compared four strains of Streptomyces isolated from insect herbivores that attack pine trees: S. sp. DpondAA-B6 (SDPB6) from the mountain pine beetle; S. sp. SPB74 from the southern pine beetle; and S. sp. SirexAA-E (SACTE) and S. sp. SirexAA-G from the woodwasp, Sirex noctilio. Biochemical analysis of secreted enzymes demonstrated that only two of these strains, SACTE and SDPB6, were efficient at degrading plant biomass. Genomic analyses indicated that SACTE and SDPB6 are closely phylogenetically related and that they share similar compositions of carbohydrate active enzymes. Genome-wide proteomic and transcriptomic analyses revealed that the major exocellulases (GH6 and GH48), lytic polysaccharide monooxygenases (AA10), and mannanases (GH5) were conserved and secreted in both organisms, while the secreted endocellulases (GH5 and GH9 versus GH9 and GH12) were from diverged enzyme families. Together, these data identify two phylogenetically related insect-associated Streptomyces strains with high biomass degrading activity and characterize key enzymatic similarities and differences used by these organisms to deconstruct plant biomass.
    Applied and Environmental Microbiology 05/2014; 80(15). DOI:10.1128/AEM.01133-14 · 3.95 Impact Factor

Publication Stats

21k Citations
4,241.00 Total Impact Points

Institutions

  • 2004–2015
    • Harvard Medical School
      • Department of Biological Chemistry and Molecular Pharmacology
      Boston, Massachusetts, United States
  • 2014
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1977–2014
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 2011
    • University of Lisbon
      • Institute of Molecular Medicine
      Lisboa, Lisbon, Portugal
  • 2007–2011
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
    • The Rockefeller University
      • Laboratory of Genetically Encoded Small Molecules
      New York City, NY, United States
  • 1977–2011
    • Cornell University
      • Department of Chemistry and Chemical Biology
      Итак, New York, United States
  • 2010
    • Cheikh Anta Diop University, Dakar
      Dakar, Dakar, Senegal
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2004–2010
    • Shizuoka University
      • • Faculty of Engineering
      • • Department of Applied Biological Chemistry
      Sizuoka, Shizuoka, Japan
  • 1979–2010
    • Mahidol University
      • • Department of Chemistry
      • • Department of Pharmacology ( Science)
      Krung Thep, Bangkok, Thailand
  • 2009
    • Yale University
      • Department of Chemistry
      New Haven, CT, United States
  • 1994–2004
    • University of California, Santa Cruz
      • Department of Chemistry & Biochemistry
      Santa Cruz, CA, United States
  • 1993–2002
    • University of San Diego
      San Diego, California, United States
    • Chulalongkorn University
      • Department of Chemistry
      Krung Thep, Bangkok, Thailand
  • 1996
    • Bristol-Myers Squibb
      New York City, New York, United States
  • 1995
    • University of Washington Seattle
      Seattle, Washington, United States
    • University of Colombo
      Columbo, Western, Sri Lanka
    • Chittaranjan National Cancer Institute
      Kolkata, West Bengal, India
  • 1992
    • University of Alberta
      • Department of Chemistry
      Edmonton, Alberta, Canada
  • 1989–1990
    • University of Illinois at Chicago
      • College of Pharmacy
      Chicago, IL, United States
    • Thompson Institute
      Итак, New York, United States
    • Tottori University
      TTJ, Tottori, Japan
  • 1987
    • University of Concepción
      Ciudad de Concepcion, Biobío, Chile
    • Meijo University
      Nagoya, Aichi, Japan
  • 1984–1987
    • Universidad de La Laguna
      San Cristóbal de La Laguna, Canary Islands, Spain
    • Montana State University
      Бозмана, Montana, United States
  • 1972–1979
    • Iowa State University
      • Department of Chemistry
      Ames, IA, United States