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Cell Chemical Biology

Ken Ishikawa, Scott H Medina, Joel P Schneider, Amar J S Klar
Although resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Anticancer peptides (ACPs) are a class of such agents that disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance toward ACPs is unlikely to occur. We demonstrate that eukaryotic cells can, indeed, develop resistance to the model oncolytic peptide SVS-1, which preferentially disrupts the membranes of cancer cells...
January 9, 2017: Cell Chemical Biology
Katharina Rox, Manfred Rohde, Gursharan Singh Chhatwal, Rolf Müller
Bacterial pathogens use invasion into human cells as a strategy to escape not only the host's immune response, but also anti-bacterial treatment. This often leads to persistence and enables reinitiation of the infection process at a later time point. Here, we show that a family of myxobacterial metabolites, disorazoles, block invasion of group A Streptococcus (GAS) into human epithelial cells. Mechanistically, disorazoles target ezrin, a host protein involved in linking microfilaments to the membrane, and affect invasion most likely by interfering with dynamic phosphorylation of ezrin...
January 5, 2017: Cell Chemical Biology
Yongqi Shao, Bosheng Chen, Chao Sun, Keishi Ishida, Christian Hertweck, Wilhelm Boland
Insects develop efficient antimicrobial strategies to flourish in a bacterial world. It has long been proposed that native gut microbiota is an important component of host defense; however, the responsible species have rarely been isolated to elucidate the mechanism of action. Here we show that the dominant symbiotic bacterium Enterococcus mundtii associated with the generalist herbivore Spodoptera littoralis actively secretes a stable class IIa bacteriocin (mundticin KS) against invading bacteria, but not against other gut residents, facilitating the normal development of host gut microbiota...
January 19, 2017: Cell Chemical Biology
Daniel Braga, Gerald Lackner
In this issue of Cell Chemical Biology, Li et al. (2017) report on the biosynthesis of the monobactam sulfazecin by Pseudomonas acidophila and hypothesize a novel mechanism of β-lactam ring formation. As monobactam antibiotics are unaffected by some emerging resistance mechanisms (particularly metallo-β-lactamases), this discovery opens prospects to engineer β-lactam antibiotics against multi-drug resistant pathogens.
January 19, 2017: Cell Chemical Biology
Boyuan Wang, Aishan Zhao, Qian Xie, Paul Dominic Olinares, Brian T Chait, Richard P Novick, Tom W Muir
Staphylococcus aureus employs the receptor histidine kinase (RHK), AgrC, to detect quorum-sensing (QS) pheromones, the autoinducer peptides (AIPs), which regulate the virulence of the bacterium. Variation in the QS circuit divides S. aureus into four subgroups, each producing a specific AIP-AgrC pair. While the timing of QS induction is known to differ among these subgroups, the molecular basis of this phenomenon is unknown. Here, we report the successful reconstitution of several AgrC variants and show that the agonist-induced activity of the receptors varies in a manner that accounts for these temporal differences in QS induction...
January 19, 2017: Cell Chemical Biology
Natalya Gertsik, Christopher W Am Ende, Kieran F Geoghegan, Chuong Nguyen, Paramita Mukherjee, Scot Mente, Uthpala Seneviratne, Douglas S Johnson, Yue-Ming Li
γ-Secretase, a four-subunit transmembrane aspartic proteinase, is a highly valued drug target in Alzheimer's disease and cancer. Despite significant progress in structural studies, the respective molecular mechanisms and binding modes of γ-secretase inhibitors (GSIs) and modulators (GSMs) remain uncertain. Here, we developed biotinylated cleavable-linker photoprobes based on the BMS-708163 GSI to study its interaction with γ-secretase. Comparison of four cleavable linkers indicated that the hydrazine-labile N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) linker was cleaved most efficiently to release photolabeled and affinity-captured presenilin-1 (PS1), the catalytic subunit of γ-secretase...
January 19, 2017: Cell Chemical Biology
Jeannie L Hernandez, Dahvid Davda, Melanie Cheung See Kit, Jaimeen D Majmudar, Sang Joon Won, Margery Gang, Sirisha C Pasupuleti, Alexandria I Choi, Callie M Bartkowiak, Brent R Martin
The multidomain scaffolding protein Scribble (Scrib) organizes key signaling complexes to specify basolateral cell polarity and suppress aberrant growth. In many human cancers, genetically normal Scrib mislocalizes from cell-cell junctions to the cytosol, correlating with enhanced growth signaling and malignancy. Here we confirm that expression of the epithelial-to-mesenchymal transcription factor (EMT-TF) Snail in benign epithelial cells leads to Scrib displacement from the plasma membrane, mimicking the mislocalization observed in aggressive cancers...
January 19, 2017: Cell Chemical Biology
Kalpana Makhijani, Tsz-Leung To, Rubén Ruiz-González, Céline Lafaye, Antoine Royant, Xiaokun Shu
Cell ablation is a strategy to study cell lineage and function during development. Optogenetic methods are an important cell-ablation approach, and we have previously developed a mini singlet oxygen generator (miniSOG) tool that works in the living Caenorhabditis elegans. Here, we use directed evolution to generate miniSOG2, an improved tool for cell ablation via photogenerated reactive oxygen species. We apply miniSOG2 to a far more complex model animal system, Drosophila melanogaster, and demonstrate that it can be used to kill a single neuron in a Drosophila larva...
January 19, 2017: Cell Chemical Biology
Qian Wang, Maria V Liberti, Pei Liu, Xiaobing Deng, Ying Liu, Jason W Locasale, Luhua Lai
Metabolic reprogramming in cancer cells facilitates growth and proliferation. Increased activity of the serine biosynthetic pathway through the enzyme phosphoglycerate dehydrogenase (PHGDH) contributes to tumorigenesis. With a small substrate and a weak binding cofactor, (NAD(+)), inhibitor development for PHGDH remains challenging. Instead of targeting the PHGDH active site, we computationally identified two potential allosteric sites and virtually screened compounds that can bind to these sites. With subsequent characterization, we successfully identified PHGDH non-NAD(+)-competing allosteric inhibitors that attenuate its enzyme activity, selectively inhibit de novo serine synthesis in cancer cells, and reduce tumor growth in vivo...
January 19, 2017: Cell Chemical Biology
Jerome C Nwachukwu, Sathish Srinivasan, Nelson E Bruno, Jason Nowak, Nicholas J Wright, Filippo Minutolo, Erumbi S Rangarajan, Tina Izard, Xin-Qui Yao, Barry J Grant, Douglas J Kojetin, Olivier Elemento, John A Katzenellenbogen, Kendall W Nettles
Environmental estrogens and anti-hormone therapies for breast cancer have diverse tissue- and signaling-pathway-selective outcomes, but how estrogen receptor alpha (ERα) mediates this phenotypic diversity is poorly understood. We implemented a statistical approach to allow unbiased, parallel analyses of multiple crystal structures, and identified subtle perturbations of ERα structure by different synthetic and environmental estrogens. Many of these perturbations were in the sub-Å range, within the noise of the individual structures, but contributed significantly to the activities of synthetic and environmental estrogens...
January 19, 2017: Cell Chemical Biology
Takayuki Katoh, Kenya Tajima, Hiroaki Suga
Recent progress in the field of genetic code reprogramming using a reconstituted cell-free translation system has made it possible to incorporate a wide array of non-proteinogenic amino acids, including N-methyl-amino acids and D-amino acids. Despite the fact that up to ten N-methyl-amino acid residues can be continuously elongated, the successive incorporation of even two D-amino acids into a nascent peptide chain remains a formidable challenge, thus far being nearly impossible. Here we report achievement of continuous D-amino acid elongation by the use of engineered tRNAs and optimized concentrations of translation factors, enabling us to incorporate up to ten consecutive D-Ser residues into a nascent peptide chain...
January 19, 2017: Cell Chemical Biology
Georgina Cox, Arthur Sieron, Andrew M King, Gianfranco De Pascale, Andrew C Pawlowski, Kalinka Koteva, Gerard D Wright
Solving the antibiotic resistance crisis requires the discovery of new antimicrobial drugs and the preservation of existing ones. The discovery of inhibitors of antibiotic resistance, antibiotic adjuvants, is a proven example of the latter. A major difficulty in identifying new antibiotics is the frequent rediscovery of known compounds, necessitating laborious "dereplication" to identify novel chemical entities. We have developed an antibiotic resistance platform (ARP) that can be used for both the identification of antibiotic adjuvants and for antibiotic dereplication...
January 19, 2017: Cell Chemical Biology
Rongfeng Li, Ryan A Oliver, Craig A Townsend
The monobactams, exemplified by the natural product sulfazecin, are the only class of β-lactam antibiotics not inactivated by metallo-β-lactamases, which confer bacteria with extended-spectrum β-lactam resistance. We screened a transposon mutagenesis library from Pseudomonas acidophila ATCC 31363 and isolated a sulfazecin-deficient mutant that revealed a gene cluster encoding two non-ribosomal peptide synthetases (NRPSs), a methyltransferase, a sulfotransferase, and a dioxygenase. Three modules and an aberrant C-terminal thioesterase (TE) domain are distributed across the two NRPSs...
January 19, 2017: Cell Chemical Biology
Heidi Olzscha, Oleg Fedorov, Benedikt M Kessler, Stefan Knapp, Nicholas B La Thangue
Lysine acetylation is becoming increasingly recognized as a general biological principle in cellular homeostasis, and is subject to abnormal control in different human pathologies. Here, we describe a global effect on amyloid-like protein aggregation in human cells that results from aberrant lysine acetylation. Bromodomain reader proteins are involved in the aggregation process and, using chemical biology and gene silencing, we establish that p300/CBP bromodomains are necessary for aggregation to occur. Moreover, protein aggregation disturbs proteostasis by impairing the ubiquitin proteasome system (UPS) and protein translation, resulting in decreased cell viability...
January 19, 2017: Cell Chemical Biology
Vered Padler-Karavani
Advances in genomics and bioinformatics facilitated identification of tumor-specific neoantigens as optimal targets for cancer immunotherapy. In this hot topic, most efforts focus on mutant peptide antigens, overlooking tumor-associated glycosylation changes. Given the latest progress in glycomics, in this issue of Cell Chemical Biology, Xia et al. (2016) use glyco-antigen microarrays to investigate immune responses to whole cancer vaccines and provide important insights into vaccine efficacy.
December 22, 2016: Cell Chemical Biology
Dominic A Colosimo, John B MacMillan
In this issue of Cell Chemical Biology, Jordan and Moore (2016) present a thorough biosynthetic analysis of ammosamides, a bacterial natural product. The work highlights the previously unknown overlap between two natural products families: pyrroloquinoline alkaloids and ribosomally synthesized posttranslationally modified peptides (RiPPs).
December 22, 2016: Cell Chemical Biology
Craig L Doig, Gareth G Lavery
Successful phase III trials with poly-ADP-ribose (PARP) inhibitors will have implications for stratified cancer therapy. In this issue of Cell Chemical Biology, Knezevic et al. (2016) demonstrate that the existing collection of PARP inhibitors each display distinctive protein interaction profiles, reaching beyond their intended therapeutic target, with implications for metabolic and other disease.
December 22, 2016: Cell Chemical Biology
Cynthia K Holland, Barbara Cascella, Joseph M Jez
In this issue of Cell Chemical Biology, Mori et al. (2016) combine X-ray crystallography and biochemistry to discover a new mechanism for stilbene synthesis in bacteria. The dialkyl-condensing enzyme StlD catalyzes formation of cyclohexanediones using a non-canonical β-ketosynthase active site. Aromatization by StlC completes production of the stilbene product.
December 22, 2016: Cell Chemical Biology
Milka Kostic
No abstract text is available yet for this article.
December 22, 2016: Cell Chemical Biology
Stephanie M Reeve, Eric W Scocchera, Narendran G-Dayanadan, Santosh Keshipeddy, Jolanta Krucinska, Behnoush Hajian, Jacob Ferreira, Michael Nailor, Jeffrey Aeschlimann, Dennis L Wright, Amy C Anderson
Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and to develop new agents that overcome those mechanisms. The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics. However, resistance through chromosomal mutations and mobile, plasmid-encoded insensitive DHFRs threatens the continued use of this agent. We are pursuing the development of new propargyl-linked antifolate (PLA) DHFR inhibitors designed to evade these mechanisms...
December 22, 2016: Cell Chemical Biology
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