Abstract：
:Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Rather than focusing on therapeutics that target in vitro viability, much like conventional antibiotics, an alternative approach is to target functions essential for infection, such as virulence factors required to cause host damage and disease. This approach has several potential advantages including expanding the repertoire of bacterial targets, preserving the host endogenous microbiome, and exerting less selective pressure, which may result in decreased resistance. We review new approaches to targeting virulence, discuss their advantages and disadvantages, and propose that in addition to targeting virulence, new antimicrobial development strategies should be expanded to include targeting bacterial gene functions that are essential for in vivo viability. We highlight both new advances in identifying these functions and prospects for antimicrobial discovery targeting this unexploited area.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Clatworthy AE,Pierson E,Hung DTdoi
10.1038/nchembio.2007.24subject
Has Abstractpub_date
2007-09-01 00:00:00pages
541-8issue
9eissn
1552-4450issn
1552-4469pii
nchembio.2007.24journal_volume
3pub_type
杂志文章,评审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：:Genetic screens in cultured human cells represent a powerful unbiased strategy to identify cellular pathways that determine drug efficacy, providing critical information for clinical development. We used insertional mutagenesis-based screens in haploid cells to identify genes required for the sensitivity to lasonolide...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0447-7
更新日期：2020-02-01 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：:The resistance of Caenorhabditis elegans to pharmacological perturbation limits its use as a screening tool for novel small bioactive molecules. One strategy to improve the hit rate of small-molecule screens is to preselect molecules that have an increased likelihood of reaching their target in the worm. To learn whic...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.380
更新日期：2010-07-01 00:00:00
abstract：:Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.694
更新日期：2011-10-30 00:00:00
abstract：:Bacteria are thought to cope with fluctuating environmental solute concentrations primarily by adjusting the osmolality of their cytoplasm. To obtain insights into the underlying metabolic adaptations, we analyzed the global metabolic response of Escherichia coli to sustained hyperosmotic stress using nontargeted mass...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1437
更新日期：2014-04-01 00:00:00
abstract：:Identification of endogenous glycan-binding ligands for cell-surface receptors has been difficult. Incorporation of a photoactive sialic acid analog into B-cell surface glycoproteins suggests that CD22 molecules may cluster by binding carbohydrate antigens on neighboring CD22 molecules. ...
journal_title：Nature chemical biology
pub_type： 评论,新闻
doi：10.1038/nchembio0705-69
更新日期：2005-07-01 00:00:00
abstract：:Biodiversity, or the relative abundance of species, measures the persistence of an ecosystem. To better understand its modulation, we analyzed the spatial and temporal dynamics of a synthetic, chemical-mediated ecosystem that consisted of two engineered Escherichia coli populations. Depending on the specific experimen...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.244
更新日期：2009-12-01 00:00:00
abstract：:Subtilosin A is a 35-residue, ribosomally synthesized bacteriocin encoded by the sbo-alb operon of Bacillus subtilis. It is composed of a head-to-tail circular peptide backbone that is additionally restrained by three unusual thioether bonds between three cysteines and the α-carbon of one threonine and two phenylalani...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.798
更新日期：2012-02-26 00:00:00
abstract：:Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2251
更新日期：2017-02-01 00:00:00
abstract：:Conditional cooperativity is a common mechanism involved in transcriptional regulation of prokaryotic type II toxin-antitoxin operons and is intricately related to bacterial persistence. It allows the toxin component of a toxin-antitoxin module to act as a co-repressor at low doses of toxin as compared to antitoxin. W...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2078
更新日期：2016-07-01 00:00:00
abstract：:We engineered a photoactivatable system for rapidly and reversibly exporting proteins from the nucleus by embedding a nuclear export signal in the LOV2 domain from phototropin 1. Fusing the chromatin modifier Bre1 to the photoswitch, we achieved light-dependent control of histone H2B monoubiquitylation in yeast, revea...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2068
更新日期：2016-06-01 00:00:00
abstract：:In this study, we demonstrate the feasibility of expanding the genetic code of Escherichia coli using its own tryptophanyl-tRNA synthetase and tRNA (TrpRS-tRNATrp) pair. This was made possible by first functionally replacing this endogenous pair with an E. coli-optimized counterpart from Saccharomyces cerevisiae, and ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2312
更新日期：2017-04-01 00:00:00
abstract：: ...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章
doi：10.1038/s41589-018-0174-5
更新日期：2018-12-01 00:00:00
abstract：:Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-020-0496-y
更新日期：2020-05-01 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：:N6-Methyladenosine (m6A) RNA modification is present in messenger RNAs (mRNA), ribosomal RNAs (rRNA), and spliceosomal RNAs (snRNA) in humans. Although mRNA m6A modifications have been extensively studied and shown to play critical roles in many cellular processes, the identity of m6A methyltransferases for rRNAs and ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0184-3
更新日期：2019-01-01 00:00:00
abstract：:Proper gene expression is essential for the survival of every cell. Once thought to be a passive transporter of genetic information, RNA has recently emerged as a key player in nearly every pathway in the cell. A full description of its structure is critical to understanding RNA function. Decades of research have focu...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1958
更新日期：2015-12-01 00:00:00
abstract：:Using linewidth and spinning sideband intensities of lipid hydrocarbon chain resonances in proton magic angle spinning NMR spectra, we detected the temperature-dependent phase state of naturally occurring lipids of intact influenza virus without exogenous probes. Increasingly, below 41 degrees C ordered and disordered...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.77
更新日期：2008-04-01 00:00:00
abstract：:The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2148
更新日期：2016-10-01 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：:Many protein kinases are key nodal signaling molecules that regulate a wide range of cellular functions. These functions may require complex spatiotemporal regulation of kinase activities. Here, we show that protein kinase A (PKA), Ca(2+) and cyclic AMP (cAMP) oscillate in sync in insulin-secreting MIN6 beta cells, fo...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.478
更新日期：2011-01-01 00:00:00
abstract：:The actin cytoskeleton supports diverse cellular processes such as endocytosis, oriented growth, adhesion and migration. The dynamic nature of the cytoskeleton, however, has made it difficult to define the roles of the many accessory molecules that modulate actin organization, especially the multifunctional adapter pr...
journal_title：Nature chemical biology
pub_type： 信件
doi：10.1038/nchembio755
更新日期：2006-01-01 00:00:00
abstract：:Synthetic mRNA is an attractive vehicle for gene therapies because of its transient nature and improved safety profile over DNA. However, unlike DNA, broadly applicable methods to control expression from mRNA are lacking. Here we describe a platform for small-molecule-based regulation of expression from modified RNA (...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0146-9
更新日期：2018-11-01 00:00:00
abstract：:The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. I...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2168
更新日期：2016-11-01 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：: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：:Plants have recently moved into the spotlight owing to the growing realization that the world needs solutions to energy and food production that are sustainable and environmentally sound. Iron, copper and zinc are essential for plant growth and development, yet the same properties that make these transition metals ind...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.166
更新日期：2009-05-01 00:00:00
abstract：:Beyond established roles in collagen biosynthesis, hypoxic signaling and fatty acid metabolism, recent reports have now revealed roles for human 2-oxoglutarate-dependent oxygenases in histone and nucleic acid demethylation and in signaling protein hydroxylation. The emerging role of these oxygenases in enabling a mult...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio0308-152
更新日期：2008-03-01 00:00:00
abstract：:More than 30 years ago, a calcium-dependent enzyme activity was described that generates N-acyl phosphatidylethanolamines (NAPEs), which are precursors for N-acyl ethanolamine (NAE) lipid transmitters, including the endocannabinoid anandamide. The identity of this calcium-dependent N-acyltransferase (Ca-NAT) has remai...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2127
更新日期：2016-09-01 00:00:00
