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Using genomics to deliver natural products from symbiotic bacteria
Jon Clardy
Genome Biology , 2005, DOI: 10.1186/gb-2005-6-9-232
Abstract: Natural products - small molecules derived from living organisms - have long been objects of fascination and utility, and they have provided most of the motivation for developing organic chemistry [1]. An example is given by morphine, the most active of the sleep-inducing compounds in opium, which was isolated in pure form in 1806 but was known thousands of years earlier [2]. Collaboration between chemists and biologists led to the identification of the opioid receptor and the isolation of its endogenous ligands (enkephalins). The story of morphine and related compounds has been repeated many times, and natural-products research still contributes important small molecules to medicine. Between 2000 and 2003, 15 new drugs derived from natural products were introduced for the treatment of disorders such as malaria, fungal infections, bacterial infections, cancer, blood clots, premature labor, infertility, and stimulation of the central nervous system, such as Alzheimer's disease [3,4]. Two recent papers [5,6] describe the identification and cloning of genes encoding the biosynthetic pathway of patellamide, a potential anticancer agent, highlighting the profound changes that genomic approaches are bringing about in what is arguably the oldest scientific discipline.Natural-products research was transformed in the 1940s by the establishment of the actinomycete group of Gram-positive filamentous soil bacteria as the premier source of medically useful natural products. The actinomycete group produces the antibiotics streptomycin, actinomycin, erythromycin, and vancomycin; the antifungal agents nystatin and amphotericin; the anticancer agents doxorubicin and calicheamicin; the immunosuppressive agents FK506 and rapamycin; and many other useful molecules. In addition to their ability to produce this staggering array of important natural products, the biosynthetic genes of bacteria have an organization that has greatly simplified genetic studies: all of the instructions for ma
The Next Opportunity in Anti-Malaria Drug Discovery: The Liver Stage
Emily R. Derbyshire,Maria M. Mota,Jon Clardy
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002178
Citral Sensing by TRANSient Receptor Potential Channels in Dorsal Root Ganglion Neurons
Stephanie C. Stotz, Joris Vriens, Derek Martyn, Jon Clardy, David E. Clapham
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002082
Abstract: Transient receptor potential (TRP) ion channels mediate key aspects of taste, smell, pain, temperature sensation, and pheromone detection. To deepen our understanding of TRP channel physiology, we require more diverse pharmacological tools. Citral, a bioactive component of lemongrass, is commonly used as a taste enhancer, as an odorant in perfumes, and as an insect repellent. Here we report that citral activates TRP channels found in sensory neurons (TRPV1 and TRPV3, TRPM8, and TRPA1), and produces long-lasting inhibition of TRPV1–3 and TRPM8, while transiently blocking TRPV4 and TRPA1. Sustained citral inhibition is independent of internal calcium concentration, but is state-dependent, developing only after TRP channel opening. Citral's actions as a partial agonist are not due to cysteine modification of the channels nor are they a consequence of citral's stereoisoforms. The isolated aldehyde and alcohol cis and trans enantiomers (neral, nerol, geranial, and geraniol) each reproduce citral's actions. In juvenile rat dorsal root ganglion neurons, prolonged citral inhibition of native TRPV1 channels enabled the separation of TRPV2 and TRPV3 currents. We find that TRPV2 and TRPV3 channels are present in a high proportion of these neurons (94% respond to 2-aminoethyldiphenyl borate), consistent with our immunolabeling experiments and previous in situ hybridization studies. The TRPV1 activation requires residues in transmembrane segments two through four of the voltage-sensor domain, a region previously implicated in capsaicin activation of TRPV1 and analogous menthol activation of TRPM8. Citral's broad spectrum and prolonged sensory inhibition may prove more useful than capsaicin for allodynia, itch, or other types of pain involving superficial sensory nerves and skin.
Chemical Analyses of Wasp-Associated Streptomyces Bacteria Reveal a Prolific Potential for Natural Products Discovery
Michael Poulsen,Dong-Chan Oh,Jon Clardy,Cameron R. Currie
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016763
Abstract: Identifying new sources for small molecule discovery is necessary to help mitigate the continuous emergence of antibiotic-resistance in pathogenic microbes. Recent studies indicate that one potentially rich source of novel natural products is Actinobacterial symbionts associated with social and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15 of these isolates identified 11 distinct and structurally diverse secondary metabolites, including a novel polyunsaturated and polyoxygenated macrocyclic lactam, which we name sceliphrolactam. By pairing the 15 Streptomyces strains against a collection of fungi and bacteria, we document their antifungal and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding phylogenetically diverse and chemically prolific Actinobacteria from solitary wasps suggests that insect-associated Actinobacteria can provide a valuable source of novel natural products of pharmaceutical interest.
A Sexually Conditioned Switch of Chemosensory Behavior in C. elegans
Naoko Sakai, Ryo Iwata, Saori Yokoi, Rebecca A. Butcher, Jon Clardy, Masahiro Tomioka, Yuichi Iino
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068676
Abstract: In sexually reproducing animals, mating is essential for transmitting genetic information to the next generation and therefore animals have evolved mechanisms for optimizing the chance of successful mate location. In the soil nematode C. elegans, males approach hermaphrodites via the ascaroside pheromones, recognize hermaphrodites when their tails contact the hermaphrodites' body, and eventually mate with them. These processes are mediated by sensory signals specialized for sexual communication, but other mechanisms may also be used to optimize mate location. Here we describe associative learning whereby males use sodium chloride as a cue for hermaphrodite location. Both males and hermaphrodites normally avoid sodium chloride after associative conditioning with salt and starvation. However, we found that males become attracted to sodium chloride after conditioning with salt and starvation if hermaphrodites are present during conditioning. For this conditioning, which we call sexual conditioning, hermaphrodites are detected by males through pheromonal signaling and additional cue(s). Sex transformation experiments suggest that neuronal sex of males is essential for sexual conditioning. Altogether, these results suggest that C. elegans males integrate environmental, internal and social signals to determine the optimal strategy for mate location.
Integrating Course and Instructional Evaluation with a Learning History Approach
Alan Clardy
The Journal of Scholarship of Teaching and Learning , 2003,
Identification of Anziaic Acid, a Lichen Depside from Hypotrachyna sp., as a New Topoisomerase Poison Inhibitor
Bokun Cheng, Shugeng Cao, Victor Vasquez, Thirunavukkarasu Annamalai, Giselle Tamayo-Castillo, Jon Clardy, Yuk-Ching Tse-Dinh
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060770
Abstract: Topoisomerase inhibitors are effective for antibacterial and anticancer therapy because they can lead to the accumulation of the intermediate DNA cleavage complex formed by the topoisomerase enzymes, which trigger cell death. Here we report the application of a novel enzyme-based high-throughput screening assay to identify natural product extracts that can lead to increased accumulation of the DNA cleavage complex formed by recombinant Yersinia pestis topoisomerase I as part of a larger effort to identify new antibacterial compounds. Further characterization and fractionation of the screening positives from the primary assay led to the discovery of a depside, anziaic acid, from the lichen Hypotrachyna sp. as an inhibitor for both Y. pestis and Escherichia coli topoisomerase I. In in vitro assays, anziaic acid exhibits antibacterial activity against Bacillus subtilis and a membrane permeable strain of E. coli. Anziaic acid was also found to act as an inhibitor of human topoisomerase II but had little effect on human topoisomerase I. This is the first report of a depside with activity as a topoisomerase poison inhibitor and demonstrates the potential of this class of natural products as a source for new antibacterial and anticancer compounds.
Catecholate Siderophores Protect Bacteria from Pyochelin Toxicity
Conrado Adler, Natalia S. Corbalán, Mohammad R. Seyedsayamdost, María Fernanda Pomares, Ricardo E. de Cristóbal, Jon Clardy, Roberto Kolter, Paula A. Vincent
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046754
Abstract: Background Bacteria produce small molecule iron chelators, known as siderophores, to facilitate the acquisition of iron from the environment. The synthesis of more than one siderophore and the production of multiple siderophore uptake systems by a single bacterial species are common place. The selective advantages conferred by the multiplicity of siderophore synthesis remains poorly understood. However, there is growing evidence suggesting that siderophores may have other physiological roles besides their involvement in iron acquisition. Methods and Principal Findings Here we provide the first report that pyochelin displays antibiotic activity against some bacterial strains. Observation of differential sensitivity to pyochelin against a panel of bacteria provided the first indications that catecholate siderophores, produced by some bacteria, may have roles other than iron acquisition. A pattern emerged where only those strains able to make catecholate-type siderophores were resistant to pyochelin. We were able to associate pyochelin resistance to catecholate production by showing that pyochelin-resistant Escherichia coli became sensitive when biosynthesis of its catecholate siderophore enterobactin was impaired. As expected, supplementation with enterobactin conferred pyochelin resistance to the entE mutant. We observed that pyochelin-induced growth inhibition was independent of iron availability and was prevented by addition of the reducing agent ascorbic acid or by anaerobic incubation. Addition of pyochelin to E. coli increased the levels of reactive oxygen species (ROS) while addition of ascorbic acid or enterobactin reduced them. In contrast, addition of the carboxylate-type siderophore, citrate, did not prevent pyochelin-induced ROS increases and their associated toxicity. Conclusions We have shown that the catecholate siderophore enterobactin protects E. coli against the toxic effects of pyochelin by reducing ROS. Thus, it appears that catecholate siderophores can behave as protectors of oxidative stress. These results support the idea that siderophores can have physiological roles aside from those in iron acquisition.
Selection for High Oridonin Yield in the Chinese Medicinal Plant Isodon (Lamiaceae) Using a Combined Phylogenetics and Population Genetics Approach
Eric S. J. Harris, Shugeng Cao, Sean D. Schoville, Chengming Dong, Wenquan Wang, Zaiyou Jian, Zhongzhen Zhao, David M. Eisenberg, Jon Clardy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050753
Abstract: Oridonin is a diterpenoid with anti-cancer activity that occurs in the Chinese medicinal plant Isodon rubescens and some related species. While the bioactivity of oridonin has been well studied, the extent of natural variation in the production of this compound is poorly known. This study characterizes natural variation in oridonin production in order to guide selection of populations of Isodon with highest oridonin yield. Different populations of I. rubescens and related species were collected in China, and their offspring were grown in a greenhouse. Samples were examined for oridonin content, genotyped using 11 microsatellites, and representatives were sequenced for three phylogenetic markers (ITS, rps16, trnL-trnF). Oridonin production was mapped on a molecular phylogeny of the genus Isodon using samples from each population as well as previously published Genbank sequences. Oridonin has been reported in 12 out of 74 species of Isodon examined for diterpenoids, and the phylogeny indicates that oridonin production has arisen at least three times in the genus. Oridonin production was surprisingly consistent between wild-collected parents and greenhouse-grown offspring, despite evidence of gene flow between oridonin-producing and non-producing populations of Isodon. Additionally, microsatellite genetic distance between individuals was significantly correlated with chemical distance in both parents and offspring. Neither heritability nor correlation with genetic distance were significant when the comparison was restricted to only populations of I. rubescens, but this result should be corroborated using additional samples. Based on these results, future screening of Isodon populations for oridonin yield should initially prioritize a broad survey of all species known to produce oridonin, rather than focusing on multiple populations of one species, such as I. rubescens. Of the samples examined here, I. rubescens or I. japonicus from Henan province would provide the best source of oridonin.
A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity
Patrick Ymele-Leki, Shugeng Cao, Jared Sharp, Kathleen G. Lambert, Alexander J. McAdam, Robert N. Husson, Giselle Tamayo, Jon Clardy, Paula I. Watnick
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031307
Abstract: Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples.
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