Dataset Information

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

ABSTRACT: Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

SUBMITTER: Kearney SE

PROVIDER: S-EPMC6311695 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

Kearney Sara E SE Zahoránszky-Kőhalmi Gergely G Brimacombe Kyle R KR Henderson Mark J MJ Lynch Caitlin C Zhao Tongan T Wan Kanny K KK Itkin Zina Z Dillon Christopher C Shen Min M Cheff Dorian M DM Lee Tobie D TD Bougie Danielle D Cheng Ken K Coussens Nathan P NP Dorjsuren Dorjbal D Eastman Richard T RT Huang Ruili R Iannotti Michael J MJ Karavadhi Surendra S Klumpp-Thomas Carleen C Roth Jacob S JS Sakamuru Srilatha S Sun Wei W Titus Steven A SA Yasgar Adam A Zhang Ya-Qin YQ Zhao Jinghua J Andrade Rodrigo B RB Brown M Kevin MK Burns Noah Z NZ Cha Jin K JK Mevers Emily E EE Clardy Jon J Clement Jason A JA Crooks Peter A PA Cuny Gregory D GD Ganor Jake J Moreno Jesus J Morrill Lucas A LA Picazo Elias E Susick Robert B RB Garg Neil K NK Goess Brian C BC Grossman Robert B RB Hughes Chambers C CC Johnston Jeffrey N JN Joullie Madeleine M MM Kinghorn A Douglas AD Kingston David G I DGI Krische Michael J MJ Kwon Ohyun O Maimone Thomas J TJ Majumdar Susruta S Maloney Katherine N KN Mohamed Enas E Murphy Brian T BT Nagorny Pavel P Olson David E DE Overman Larry E LE Brown Lauren E LE Snyder John K JK Porco John A JA Rivas Fatima F Ross Samir A SA Sarpong Richmond R Sharma Indrajeet I Shaw Jared T JT Xu Zhengren Z Shen Ben B Shi Wei W Stephenson Corey R J CRJ Verano Alyssa L AL Tan Derek S DS Tang Yi Y Taylor Richard E RE Thomson Regan J RJ Vosburg David A DA Wu Jimmy J Wuest William M WM Zakarian Armen A Zhang Yufeng Y Ren Tianjing T Zuo Zhong Z Inglese James J Michael Sam S Simeonov Anton A Zheng Wei W Shinn Paul P Jadhav Ajit A Boxer Matthew B MB Hall Matthew D MD Xia Menghang M Guha Rajarshi R Rohde Jason M JM

ACS central science 20181205 12

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemi ...[more]

PMID: 30648156

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Project description:Health organizations worldwide have warned that we are on the cusp of a "post-antibiotic era," necessitating new approaches to combat antibiotic resistant infections. One such approach is the development of antibiotic adjuvants, which have little or no inherent antibiotic activity at their active concentrations but instead potentiate the activity of antibiotics against antibiotic-resistant bacteria. Recently, we demonstrated that meridianin D, a natural product originally reported to have activity against Staphylococcus aureus and Mycobacterium tuberculosis, possesses the ability to reverse colistin resistance in colistin resistant bacteria. As most natural product screens typically involve screening for only certain activities (anticancer, antiviral, and antimicrobial are typical), we posited that the meridianin D discovery was not unique and there are potentially many natural products that have adjuvant activity. To explore this, the National Cancer Institute (NCI) Natural Product Library Set IV was screened for adjuvant activity using four classes of antibiotics (β-lactams, aminoglycosides, macrolides, and polymyxins) against three bacterial pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Klebsiella pneumoniae). Sixteen compounds suppressed β-lactam resistance in MRSA, five of which effected a 16-fold reduction in the oxacillin minimum inhibitory concentration (MIC). Two natural products effectively suppressed aminoglycoside resistance in both of the Gram-negative species tested, and no hits were observed with macrolides. In contrast, a larger number of natural product adjuvants were identified when screening against colistin-resistant strains of A. baumannii and K. pneumoniae. Nine compounds reduced the colistin MIC to its breakpoint or lower (up to a 1024-fold reduction). Clorobiocin, novobiocin, and prodigiosin were most effective, reducing the colistin MIC in K. pneumoniae strain B9 to 2 μg/mL at concentrations as low as 0.625, 2.5, and 1.25 μM, respectively. Restored sensitivity to colistin with these compounds does not appear to coincide with known mechanisms of colistin resistance.

Dataset Information

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

Publications

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

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