当前位置： SCI文献检索 > ACS Chemical Biology期刊下所有文献 > Linking High-Throughput Screens to Identify MoAs and Novel Inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase.

Linking High-Throughput Screens to Identify MoAs and Novel Inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase.

Abstract：

:Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Santa Maria JP Jr,Park Y,Yang L,Murgolo N,Altman MD,Zuck P,Adam G,Chamberlin C,Saradjian P,Dandliker P,Boshoff HIM,Barry CE 3rd,Garlisi C,Olsen DB,Young K,Glick M,Nickbarg E,Kutchukian PS

doi

10.1021/acschembio.7b00468

subject

Has Abstract

pub_date

2017-09-15 00:00:00

pages

2448-2456

issue

9

eissn

1554-8929

issn

1554-8937

journal_volume

12

pub_type

杂志文章

相关文献

ACS Chemical Biology文献大全
  • Chromophore-assisted light inactivation of HaloTag fusion proteins labeled with eosin in living cells.

    abstract：:Chromophore-assisted light inactivation (CALI) is a potentially powerful tool for the acute disruption of a target protein inside living cells with high spatiotemporal resolution. This technology, however, has not been widely utilized, mainly because of the lack of an efficient chromophore as the photosensitizing agen...

    journal_title：ACS chemical biology

    pub_type： 信件

    doi：10.1021/cb100431e

    authors： Takemoto K,Matsuda T,McDougall M,Klaubert DH,Hasegawa A,Los GV,Wood KV,Miyawaki A,Nagai T

    更新日期：2011-05-20 00:00:00

  • Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications.

    abstract：:Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of cysteine or serine side chains, this aldehyde-functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb500897w

    authors： Appel MJ,Bertozzi CR

    更新日期：2015-01-16 00:00:00

  • Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from Traditional High Throughput Screening.

    abstract：:N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.6b00913

    authors： Kutchukian PS,Warren L,Magliaro BC,Amoss A,Cassaday JA,O'Donnell G,Squadroni B,Zuck P,Pascarella D,Culberson JC,Cooke AJ,Hurzy D,Schlegel KS,Thomson F,Johnson EN,Uebele VN,Hermes JD,Parmentier-Batteur S,Finley M

    更新日期：2017-02-17 00:00:00

  • The STAT5b Linker Domain Mediates the Selectivity of Catechol Bisphosphates for STAT5b over STAT5a.

    abstract：:STAT family proteins are important mediators of cell signaling and represent therapeutic targets for the treatment of human diseases. Most STAT inhibitors target the protein-protein interaction domain, the SH2 domain, but specificity for a single STAT protein is often limited. Recently, we developed catechol bisphosph...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b00137

    authors： Gräb J,Berg A,Blechschmidt L,Klüver B,Rubner S,Fu DY,Meiler J,Gräber M,Berg T

    更新日期：2019-04-19 00:00:00

  • Targeting native adult heart progenitors with cardiogenic small molecules.

    abstract：:Targeting native progenitors with small molecule pharmaceuticals that direct cell fate decisions is an attractive approach for regenerative medicine. Here, we show that 3,5-disubstituted isoxazoles (Isx), stem cell-modulator small molecules originally recovered in a P19 embryonal carcinoma cell-based screen, directed ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb200525q

    authors： Russell JL,Goetsch SC,Aguilar HR,Frantz DE,Schneider JW

    更新日期：2012-06-15 00:00:00

  • A Hydrogel-Microsphere Drug Delivery System That Supports Once-Monthly Administration of a GLP-1 Receptor Agonist.

    abstract：:We have developed a chemically controlled very long-acting delivery system to support once-monthly administration of a peptidic GLP-1R agonist. Initially, the prototypical GLP-1R agonist exenatide was covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection in ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00218

    authors： Schneider EL,Hearn BR,Pfaff SJ,Reid R,Parkes DG,Vrang N,Ashley GW,Santi DV

    更新日期：2017-08-18 00:00:00

  • Trypanosomal dihydrofolate reductase reveals natural antifolate resistance.

    abstract：:Dihydrofolate reductase (DHFR) is a potential drug target for Trypanosoma brucei, a human parasite, which is the causative agent for African sleeping sickness. No drug is available against this target, since none of the classical antifolates such as pyrimethamine (PYR), cycloguanil, or trimethoprim are effective as se...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb200124r

    authors： Vanichtanankul J,Taweechai S,Yuvaniyama J,Vilaivan T,Chitnumsub P,Kamchonwongpaisan S,Yuthavong Y

    更新日期：2011-09-16 00:00:00

  • Imaging the lipidome: omega-alkynyl fatty acids for detection and cellular visualization of lipid-modified proteins.

    abstract：:Fatty acylation or lipid modification of proteins controls their cellular activation and diverse roles in physiology. It mediates protein-protein and protein-membrane interactions and plays an important role in regulating cellular signaling pathways. Currently, there is need for visualizing lipid modifications of prot...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb900085z

    authors： Hannoush RN,Arenas-Ramirez N

    更新日期：2009-07-17 00:00:00

  • A derivatized scorpion toxin reveals the functional output of heteromeric KCNQ1-KCNE K+ channel complexes.

    abstract：:KCNE transmembrane peptides are a family of modulatory beta-subunits that assemble with voltage-gated K+ channels, producing the diversity of potassium currents needed for proper function in a variety of tissues. Although all five KCNE transcripts have been found in cardiac and other tissues, it is unclear whether two...

    journal_title：ACS chemical biology

    pub_type： 信件

    doi：10.1021/cb700089s

    authors： Morin TJ,Kobertz WR

    更新日期：2007-07-20 00:00:00

  • Cell-penetrating bisubstrate-based protein kinase C inhibitors.

    abstract：:Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are t...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb300709g

    authors： van Wandelen LT,van Ameijde J,Ismail-Ali AF,van Ufford HC,Vijftigschild LA,Beekman JM,Martin NI,Ruijtenbeek R,Liskamp RM

    更新日期：2013-07-19 00:00:00

  • 2D NMR-based metabolomics uncovers interactions between conserved biochemical pathways in the model organism Caenorhabditis elegans.

    abstract：:Ascarosides are small-molecule signals that play a central role in C. elegans biology, including dauer formation, aging, and social behaviors, but many aspects of their biosynthesis remain unknown. Using automated 2D NMR-based comparative metabolomics, we identified ascaroside ethanolamides as shunt metabolites in C. ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb3004644

    authors： Izrayelit Y,Robinette SL,Bose N,von Reuss SH,Schroeder FC

    更新日期：2013-02-15 00:00:00

  • Unlocking the Spatial Control of Secondary Metabolism Uncovers Hidden Natural Product Diversity in Nostoc punctiforme.

    abstract：:Filamentous cyanobacteria belong to the most prolific producers of structurally unique and biologically active natural products, yet the majority of biosynthetic gene clusters predicted for these multicellular collectives are currently orphan. Here, we present a systems analysis of secondary metabolite gene expression...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b00240

    authors： Dehm D,Krumbholz J,Baunach M,Wiebach V,Hinrichs K,Guljamow A,Tabuchi T,Jenke-Kodama H,Süssmuth RD,Dittmann E

    更新日期：2019-06-21 00:00:00

  • Engineering Atypical Tetracycline Formation in Amycolatopsis sulphurea for the Production of Modified Chelocardin Antibiotics.

    abstract：:To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline c...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b01125

    authors： Lukežič T,Fayad AA,Bader C,Harmrolfs K,Bartuli J,Groß S,Lešnik U,Hennessen F,Herrmann J,Pikl Š,Petković H,Müller R

    更新日期：2019-03-15 00:00:00

  • Quantitative Profiling of Protein O-GlcNAcylation Sites by an Isotope-Tagged Cleavable Linker.

    abstract：:Large-scale quantification of protein O-linked β- N-acetylglucosamine (O-GlcNAc) modification in a site-specific manner remains a key challenge in studying O-GlcNAc biology. Herein, we developed an isotope-tagged cleavable linker (isoTCL) strategy, which enabled isotopic labeling of O-GlcNAc through bioorthogonal conj...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00414

    authors： Qin K,Zhu Y,Qin W,Gao J,Shao X,Wang YL,Zhou W,Wang C,Chen X

    更新日期：2018-08-17 00:00:00

  • Design and characterization of an active site selective caspase-3 transnitrosating agent.

    abstract：:The oxidative addition of nitric oxide (NO) to a thiol, S-nitrosation, is a focus of studies on cyclic guanosine monophosphate (cGMP)-independent NO signaling. S-Nitrosation of the catalytic cysteine of the caspase proteases has important effects on apoptosis and consequently has received attention. Here we report on ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb600393x

    authors： Mitchell DA,Morton SU,Marletta MA

    更新日期：2006-11-21 00:00:00

  • Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to β-lactams.

    abstract：:Rising drug resistance is limiting treatment options for infections by methicillin-resistant Staphylococcus aureus (MRSA). Herein we provide new evidence that wall teichoic acid (WTA) biogenesis is a remarkable antibacterial target with the capacity to destabilize the cooperative action of penicillin-binding proteins ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb300413m

    authors： Farha MA,Leung A,Sewell EW,D'Elia MA,Allison SE,Ejim L,Pereira PM,Pinho MG,Wright GD,Brown ED

    更新日期：2013-01-18 00:00:00

  • The Recognition of Unrelated Ligands by Identical Proteins.

    abstract：:Unrelated ligands, often found in drug discovery campaigns, can bind to the same receptor, even with the same protein residues. To investigate how this might occur, and whether it might be typically possible to find unrelated ligands for the same drug target, we sought examples of topologically unrelated ligands that ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00443

    authors： Pottel J,Levit A,Korczynska M,Fischer M,Shoichet BK

    更新日期：2018-09-21 00:00:00

  • Characterization of Sviceucin from Streptomyces Provides Insight into Enzyme Exchangeability and Disulfide Bond Formation in Lasso Peptides.

    abstract：:Lasso peptides are bacterial ribosomally synthesized and post-translationally modified peptides. They have sparked increasing interest in peptide-based drug development because of their compact, interlocked structure, which offers superior stability and protein-binding capacity. Disulfide bond-containing lasso peptide...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.5b00584

    authors： Li Y,Ducasse R,Zirah S,Blond A,Goulard C,Lescop E,Giraud C,Hartke A,Guittet E,Pernodet JL,Rebuffat S

    更新日期：2015-11-20 00:00:00

  • Chemical modification of conotoxins to improve stability and activity.

    abstract：:Conotoxins are small disulfide-rich peptides from the venom of cone snails. Along with other conopeptides, they target a wide range of membrane receptors, ion channels, and transporters, and because of their high potency and selectivity for defined subtypes of these receptors, they have attracted a great deal of atten...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb700091j

    authors： Craik DJ,Adams DJ

    更新日期：2007-07-20 00:00:00

  • Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death.

    abstract：:Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to ide...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb300653v

    authors： Adams DJ,Boskovic ZV,Theriault JR,Wang AJ,Stern AM,Wagner BK,Shamji AF,Schreiber SL

    更新日期：2013-05-17 00:00:00

  • A hexylchloride-based catch-and-release system for chemical proteomic applications.

    abstract：:Bioorthogonal ligation methods that allow the selective conjugation of fluorophores or biotin to proteins and small molecule probes that contain inert chemical handles are an important component of many chemical proteomic strategies. Here, we present a new catch-and-release enrichment strategy that utilizes a hexylchl...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb300623a

    authors： Brigham JL,Perera BG,Maly DJ

    更新日期：2013-04-19 00:00:00

  • Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.

    abstract：:The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their func...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb900083m

    authors： Ndubaku C,Varfolomeev E,Wang L,Zobel K,Lau K,Elliott LO,Maurer B,Fedorova AV,Dynek JN,Koehler M,Hymowitz SG,Tsui V,Deshayes K,Fairbrother WJ,Flygare JA,Vucic D

    更新日期：2009-07-17 00:00:00

  • Chemical Probe To Monitor the Parkinsonism-Associated Protein DJ-1 in Live Cells.

    abstract：:Reactive oxygen species (ROS) play an important role in the onset of Parkinson's disease (PD), and deciphering protective mechanisms is a major goal for therapeutic development. Here, DJ-1 (PARK7) gained major attention when a conserved cysteine residue with a putative role in oxidative stress sensing/protection was l...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00633

    authors： Drechsel J,Mandl FA,Sieber SA

    更新日期：2018-08-17 00:00:00

  • Characterization of CYP115 As a Gibberellin 3-Oxidase Indicates That Certain Rhizobia Can Produce Bioactive Gibberellin A4.

    abstract：:The gibberellin (GA) phytohormones are produced not only by plants but also by fungi and bacteria. Previous characterization of a cytochrome P450 (CYP)-rich GA biosynthetic operon found in many symbiotic, nitrogen-fixing rhizobia led to the elucidation of bacterial GA biosynthesis and implicated GA9 as the final produ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.6b01038

    authors： Nett RS,Contreras T,Peters RJ

    更新日期：2017-04-21 00:00:00

  • Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily.

    abstract：:The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the f...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00334

    authors： Wrigley JD,Gavory G,Simpson I,Preston M,Plant H,Bradley J,Goeppert AU,Rozycka E,Davies G,Walsh J,Valentine A,McClelland K,Odrzywol KE,Renshaw J,Boros J,Tart J,Leach L,Nowak T,Ward RA,Harrison T,Andrews DM

    更新日期：2017-12-15 00:00:00

  • Cytochrome c Reduction by H2S Potentiates Sulfide Signaling.

    abstract：:Hydrogen sulfide (H2S) is an endogenously produced gas that is toxic at high concentrations. It is eliminated by a dedicated mitochondrial sulfide oxidation pathway, which connects to the electron transfer chain at the level of complex III. Direct reduction of cytochrome c (Cyt C) by H2S has been reported previously b...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00463

    authors： Vitvitsky V,Miljkovic JL,Bostelaar T,Adhikari B,Yadav PK,Steiger AK,Torregrossa R,Pluth MD,Whiteman M,Banerjee R,Filipovic MR

    更新日期：2018-08-17 00:00:00

  • Humanized Lewis-Y specific antibody based delivery of STAT3 siRNA.

    abstract：:The clinical application of siRNA is limited largely by the lack of efficient, cell-specific delivery systems. Antibodies are attractive delivery vehicles for targeted therapy due to their high specificity. In this study we describe the use of a humanized monoclonal antibody (mAb), hu3S193, against Lewis-Y (Le(y)), as...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb200176v

    authors： Ma Y,Kowolik CM,Swiderski PM,Kortylewski M,Yu H,Horne DA,Jove R,Caballero OL,Simpson AJ,Lee FT,Pillay V,Scott AM

    更新日期：2011-09-16 00:00:00

  • Bacterial Riboswitches and Ribozymes Potently Activate the Human Innate Immune Sensor PKR.

    abstract：:The innate immune system provides the first line of defense against pathogens through the recognition of nonspecific patterns in RNA to protect the cell in a generalized way. The human RNA-activated protein kinase, PKR, is a dsRNA binding protein and an essential sensor in the innate immune response, which recognizes ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.6b00081

    authors： Hull CM,Anmangandla A,Bevilacqua PC

    更新日期：2016-04-15 00:00:00

  • Quantitative analysis of T cell receptor complex interaction sites using genetically encoded photo-cross-linkers.

    abstract：:The T cell receptor (TCR)-cluster of differentiation 3 (CD3) signaling complex plays an important role in initiation of adaptive immune responses, but weak interactions have obstructed delineation of the individual TCR-CD3 subunit interactions during T cell signaling. Here, we demonstrate that unnatural amino acids (U...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb500351s

    authors： Wang W,Li T,Felsovalyi K,Chen C,Cardozo T,Krogsgaard M

    更新日期：2014-09-19 00:00:00

  • Profiling Cysteine Reactivity and Oxidation in the Endoplasmic Reticulum.

    abstract：:The endoplasmic reticulum (ER) is the initial site of biogenesis of secretory pathway proteins, including proteins localized to the ER, Golgi, lysosomes, intracellular vesicles, plasma membrane, and extracellular compartments. Proteins within the secretory pathway contain a high abundance of disulfide bonds to protect...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b01014

    authors： Bechtel TJ,Li C,Kisty EA,Maurais AJ,Weerapana E

    更新日期：2020-02-21 00:00:00