Abstract：
:Identifying targets of antibacterial compounds remains a challenging step in the development of antibiotics. We have developed a two-pronged functional genomics approach to predict mechanism of action that uses mutant fitness data from antibiotic-treated transposon libraries containing both upregulation and inactivation mutants. We treated a Staphylococcus aureus transposon library containing 690,000 unique insertions with 32 antibiotics. Upregulation signatures identified from directional biases in insertions revealed known molecular targets and resistance mechanisms for the majority of these. Because single-gene upregulation does not always confer resistance, we used a complementary machine-learning approach to predict the mechanism from inactivation mutant fitness profiles. This approach suggested the cell wall precursor Lipid II as the molecular target of the lysocins, a mechanism we have confirmed. We conclude that docking to membrane-anchored Lipid II precedes the selective bacteriolysis that distinguishes these lytic natural products, showing the utility of our approach for nominating the antibiotic mechanism of action.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Santiago M,Lee W,Fayad AA,Coe KA,Rajagopal M,Do T,Hennessen F,Srisuknimit V,Müller R,Meredith TC,Walker Sdoi
10.1038/s41589-018-0041-4subject
Has Abstractpub_date
2018-06-01 00:00:00pages
601-608issue
6eissn
1552-4450issn
1552-4469pii
10.1038/s41589-018-0041-4journal_volume
14pub_type
杂志文章abstract：:Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0393-4
更新日期：2020-01-01 00:00:00
abstract：:We report here that fat mass and obesity-associated protein (FTO) has efficient oxidative demethylation activity targeting the abundant N6-methyladenosine (m(6)A) residues in RNA in vitro. FTO knockdown with siRNA led to increased amounts of m(6)A in mRNA, whereas overexpression of FTO resulted in decreased amounts of...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.687
更新日期：2011-10-16 00:00:00
abstract：:Biosynthesis enables renewable production of manifold compounds, yet often biosynthetic performance must be improved for it to be economically feasible. Nongenetic, cell-to-cell variations in protein and metabolite concentrations are naturally inherent, suggesting the existence of both high- and low-performance varian...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2046
更新日期：2016-05-01 00:00:00
abstract：:Enzyme-catalyzed peptide ligation is a powerful tool for site-specific protein bioconjugation, but stringent enzyme-substrate specificity limits its utility. We developed an approach for comprehensively characterizing peptide ligase specificity for N termini using proteome-derived peptide libraries. We used this strat...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2521
更新日期：2018-01-01 00:00:00
abstract：:Oxidase and oxygenase enzymes allow the use of relatively unreactive O2 in biochemical reactions. Many of the mechanistic strategies used in nature for this key reaction are represented within the 2-histidine-1-carboxylate facial triad family of non-heme Fe(II)-containing enzymes. The open face of the metal coordinati...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.71
更新日期：2008-03-01 00:00:00
abstract：:Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible g...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1136
更新日期：2013-02-01 00:00:00
abstract：:Bile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and immune processes by binding to host receptors. There is an unmet need for a potent tool to inhibit BSHs across all gut bacteria ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-020-0467-3
更新日期：2020-03-01 00:00:00
abstract：:Oxidation of methionine disrupts the structure and function of a range of proteins, but little is understood about the chemistry that underlies these perturbations. Using quantum mechanical calculations, we found that oxidation increased the strength of the methionine-aromatic interaction motif, a driving force for pr...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2159
更新日期：2016-10-01 00:00:00
abstract：:The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this kno...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1584
更新日期：2014-09-01 00:00:00
abstract：:Gut microbiota is found in virtually any metazoan, from invertebrates to vertebrates. It has long been believed that gut microbiota, more specifically, the activity of the microbiome and its metabolic products, directly influence a variety of aspects in metazoan physiology. However, the exact molecular relationship am...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1535
更新日期：2014-06-01 00:00:00
abstract：:RNA capping and decapping are thought to be distinctive features of eukaryotes. The redox cofactor NAD was recently discovered to be attached to small regulatory RNAs in bacteria in a cap-like manner, and Nudix hydrolase NudC was found to act as a NAD-decapping enzyme in vitro and in vivo. Here, crystal structures of ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2132
更新日期：2016-09-01 00:00:00
abstract：:Foldamers are sequence-specific oligomers akin to peptides, proteins and oligonucleotides that fold into well-defined three-dimensional structures. They offer the chemical biologist a broad pallet of building blocks for the construction of molecules that test and extend our understanding of protein folding and functio...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio876
更新日期：2007-05-01 00:00:00
abstract：:The phytohormone auxin indole-3-acetic acid (IAA) regulates nearly all aspects of plant growth and development. Despite substantial progress in our understanding of auxin biology, delineating specific auxin response remains a major challenge. Auxin regulates transcriptional response via its receptors, TIR1 and AFB F-b...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2555
更新日期：2018-03-01 00:00:00
abstract：: ...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章
doi：10.1038/s41589-018-0199-9
更新日期：2019-01-01 00:00:00
abstract：:We describe Scaffold Hunter, a highly interactive computer-based tool for navigation in chemical space that fosters intuitive recognition of complex structural relationships associated with bioactivity. The program reads compound structures and bioactivity data, generates compound scaffolds, correlates them in a hiera...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.187
更新日期：2009-08-01 00:00:00
abstract：:Cell-permeable small molecules that inhibit their targets on fast timescales are powerful probes of cell-division mechanisms. Such inhibitors have been identified using phenotype-based screens with chemical libraries. However, the characteristics of compound libraries needed to effectively span cell-division phenotype...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio826
更新日期：2006-11-01 00:00:00
abstract：:Single-molecule observations reveal that lipid- and protein-based interactions jointly contribute to the interactions among glycosylphosphatidylinositol-anchored proteins in membranes. Understanding these interactions will help to refine long-evolving (and still debated) models of 'raft' domains in biological membrane...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1045
更新日期：2012-09-01 00:00:00
abstract：:We describe a new technology for recruiting specific proteins to RNA through selective recognition of heteroduplexes formed with chemically modified antisense oligonucleotides (ASOs). Typically, ASOs function by hybridizing to their RNA targets and blocking the binding of single-stranded RNA-binding proteins. Unexpect...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.939
更新日期：2012-04-15 00:00:00
abstract：:DNA polymerases catalyze efficient and high-fidelity DNA synthesis. While this reaction favors nucleotide incorporation, polymerases also catalyze a reverse reaction, pyrophosphorolysis, that removes the DNA primer terminus and generates deoxynucleoside triphosphates. Because pyrophosphorolysis can influence polymeras...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2450
更新日期：2017-10-01 00:00:00
abstract：:The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compo...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2007.10
更新日期：2007-08-01 00:00:00
abstract：:Cell polarity is the asymmetric compartmentalization of cellular components. An opposing gradient of partitioning-defective protein kinases, atypical protein kinase C (aPKC) and PAR-1, at the cell cortex guides diverse asymmetries in the structure of metazoan cells, but the mechanism underlying their spatial patternin...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0117-1
更新日期：2018-10-01 00:00:00
abstract：:Lipid rafts in plasma membranes have emerged as possible platforms for the entry of HIV and other viruses into cells. However, little is known about how lipid phase heterogeneity contributes to viral entry because of the fine-grained and still poorly understood complexity of biological membranes. We used model systems...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1800
更新日期：2015-06-01 00:00:00
abstract：:The endocannabinoid 2-arachidonoylglycerol (2-AG) is biosynthesized by diacylglycerol lipases DAGLα and DAGLβ. Chemical probes to perturb DAGLs are needed to characterize endocannabinoid function in biological processes. Here we report a series of 1,2,3-triazole urea inhibitors, along with paired negative-control and ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1105
更新日期：2012-12-01 00:00:00
abstract：:Mitochondrial electron transport drives ATP synthesis but also generates reactive oxygen species, which are both cellular signals and damaging oxidants. Superoxide production by respiratory complex III is implicated in diverse signaling events and pathologies, but its role remains controversial. Using high-throughput ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1910
更新日期：2015-11-01 00:00:00
abstract：:Biotin is an essential vitamin in plants and mammals, functioning as the carbon dioxide carrier within central lipid metabolism. Bacterial pimeloyl-CoA synthetase (BioW) acts as a highly specific substrate-selection gate, ensuring the integrity of the carbon chain in biotin synthesis. BioW catalyzes the condensation o...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2361
更新日期：2017-06-01 00:00:00
abstract：:Linking bioactive compounds to their cellular targets is a central challenge in chemical biology. Here we report the mode of action of theonellamides, bicyclic peptides derived from marine sponges. We generated a chemical-genomic profile of theonellamide F using a collection of fission yeast strains in which each open...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.387
更新日期：2010-07-01 00:00:00
abstract：:Learning regulatory networks from genomics data is an important problem with applications spanning all of biology and biomedicine. Functional genomics projects offer a cost-effective means of greatly expanding the completeness of our regulatory models, and for some prokaryotic organisms they offer a means of learning ...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.122
更新日期：2008-11-01 00:00:00
abstract：:Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2538
更新日期：2018-02-01 00:00:00
abstract：:The catalytic versatility of cytochrome P450 monooxygenases is remarkable. Here, we present mechanistic and structural characterizations of TleB from Streptomyces blastmyceticus and its homolog HinD from Streptoalloteichus hindustanus, which catalyze unusual intramolecular C-N bond formation to generate indolactam V f...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0380-9
更新日期：2019-12-01 00:00:00
abstract：:Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in c...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2463
更新日期：2017-11-01 00:00:00
