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There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches.Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet's syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs.Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.

Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism‐of‐action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti‐cancer drugs with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein–protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin–protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on‐target and off‐target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss‐of‐fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss‐of‐function screens can elucidate mechanism‐of‐action to advance drug development. Synopsis This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response. CRISPR screens reveal important aspects of drug mechanism‐of‐action, specifically in the context of cellular activity, isoform specificity, off‐target and polypharmacological effects. By leveraging protein interaction networks that underlie drug‐responses, novel drug‐target interactions involving anti‐apoptotic MCL1 inhibitors are identified. Improved pharmacogenomic biomarker discovery using two independent and orthogonal cell viability screens. This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response.

The rapid dissemination of antibiotic resistance accelerates the desire for new antibacterial agents. Here, a class of antimicrobial peptides (AMPs) is designed by modifying the structural parameters of a natural chickpea‐derived AMP–Leg2, termed “functionalized chickpea‐derived Leg2 antimicrobial peptides” (FCLAPs). Among the FCLAPs, KTA and KTR show superior antibacterial efficacy against the foodborne pathogen Escherichia coli (E. coli) O157:H7 (with MICs in the range of 2.5–4.7 µmol L−1) and demonstrate satisfactory feasibility in alleviating E. coli O157:H7‐induced intestinal infection. Additionally, the low cytotoxicity along with insusceptibility to antimicrobial resistance increases the potential of FCLAPs as appealing antimicrobials. Combining the multi‐omics profiling andpeptide‐membrane interaction assays, a unique dual‐targeting mode of action is characterized. To specify the antibacterial mechanism, microscopical observations, membrane‐related physicochemical properties studies, and mass spectrometry assays are further performed. Data indicate that KTA and KTR induce membrane damage by initially targeting the lipopolysaccharide (LPS), thus promoting the peptides to traverse the outer membrane. Subsequently, the peptides intercalate into the peptidoglycan (PGN) layer, blocking its synthesis, and causing a collapse of membrane structure. These findings altogether imply the great potential of KTA and KTR as promising antibacterial candidates in combating the growing threat of E. coli O157:H7. Functionalized chickpea‐derived Leg2 antimicrobial peptides (FCLAPs) show superior antibacterial activity, and they combat Escherichia coli O157:H7 through a dual‐targeting mechanism. First, FCLAPs induce membrane damage by initially targeting the lipopolysaccharide, thus promoting the peptides to traverse the outer membrane. Subsequently, the peptides intercalate into the peptidoglycan layer, blocking its synthesis, and causing a collapse of membrane structure.

[Purpose/Significance] The factors and active mechanism that affect the research data sharing of faculty are investigated, and the incentive system to promote the research data sharing is proposed, which is beneficial to the occurrence of research data sharing.[Method/Process] WJX, WeChat public account and QQ are used as the research platform and the combination of questionnaires and interviews is used to analyze the influencing factors and mechanism of data sharing among faculty of local colleges. On this basis, the incentive system and strategies to improve the data sharing among faculty in local universities in China are proposed.[Results/Conclusions] The survey results show that benefits, sharing channels, sharing experiences, sharing atmosphere, and costs directly affect the data sharing among faculty, and the age, education, professional title, subject, and post indirectly affect the data sharing of faculty. By strengthening the theoretical knowledge of scientific research data sharing to improve the a

The discovery of antibiotics has been slowing to a halt. Phenotypic screening is once again at the forefront of antibiotic discovery, yet Mechanism-Of-Action (MOA) identification is still a major bottleneck. As such, methods capable of MOA elucidation coupled with the high-throughput screening of whole cells are required now more than ever, for which Fourier-Transform Infrared (FTIR) spectroscopy is a promising metabolic fingerprinting technique. A high-throughput whole-cell FTIR spectroscopy-based bioassay was developed to reveal the metabolic fingerprint induced by 15 antibiotics on the metabolism. Cells were briefly exposed to four times the minimum inhibitory concentration and spectra were quickly acquired in the high-throughput mode. After preprocessing optimization, a partial least squares discriminant analysis and principal component analysis were conducted. The metabolic fingerprints obtained with FTIR spectroscopy were sufficiently specific to allow a clear distinction between different antibiotics, across three independent cultures, with either analysis algorithm. These fingerprints were coherent with the known MOA of all the antibiotics tested, which include examples that target the protein, DNA, RNA, and cell wall biosynthesis. Because FTIR spectroscopy acquires a holistic fingerprint of the effect of antibiotics on the cellular metabolism, it holds great potential to be used for high-throughput screening in antibiotic discovery and possibly towards a better understanding of the MOA of current antibiotics.

Cancer is the second leading cause of death in the world and one of the major public health problems. Despite the great advances in cancer therapy, the incidence and mortality rates of cancer remain high. Therefore, the quest for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Curcumin, the active ingredient of the plant, has received great attention over the past two decades as an antioxidant, anti-inflammatory, and anticancer agent. In this review, a summary of the medicinal chemistry and pharmacology of curcumin and its derivatives in regard to anticancer activity, their main mechanisms of action, and cellular targets has been provided based on the literature data from the experimental and clinical evaluation of curcumin in cancer cell lines, animal models, and human subjects. In addition, the recent advances in the drug delivery systems for curcumin delivery to cancer cells have been highlighted.

There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 μg/mL—greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.

Microbes are known to colonize surfaces and form biofilms. These biofilms are communities of microbes encased in a self-produced matrix that often contains polysaccharides, DNA and proteins. Antimicrobial peptides (AMPs) have been used to control the formation and to eradicate mature biofilms. Naturally occurring or synthetic antimicrobial peptides have been shown to prevent microbial colonization of surfaces, to kill bacteria in biofilms and to disrupt the biofilm structure. This review systemically analyzed published data since 1970 to summarize the possible anti-biofilm mechanisms of AMPs. One hundred and sixty-two published reports were initially selected for this review following searches using the criteria 'antimicrobial peptide' OR 'peptide' AND 'mechanism of action' AND 'biofilm' OR 'antibiofilm' in the databases PubMed; Scopus; Web of Science; MEDLINE; and Cochrane Library. Studies that investigated anti-biofilm activities without describing the possible mechanisms were removed from the analysis. A total of 17 original reports were included which have articulated the mechanism of antimicrobial action of AMPs against biofilms. The major anti-biofilm mechanisms of antimicrobial peptides are: (1) disruption or degradation of the membrane potential of biofilm embedded cells; (2) interruption of bacterial cell signaling systems; (3) degradation of the polysaccharide and biofilm matrix; (4) inhibition of the alarmone system to avoid the bacterial stringent response; (5) downregulation of genes responsible for biofilm formation and transportation of binding proteins.

Great progress has been made in recent years to reduce the high level of suffering caused by malaria worldwide. Notably, the use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy (ACT) for malaria treatment have made a significant impact. Nevertheless, the development of resistance to the past and present anti-malarial drugs highlights the need for continued research to stay one step ahead. New drugs are needed, particularly those with new mechanisms of action. Here the range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine. A number of new potential anti-malarial drugs currently in development are outlined, along with a description of the hit to lead campaign from which it originated. Finally, promising novel mechanisms of action for these and future anti-malarial medicines are outlined.

Misuse and overuse of antibiotics have contributed in the last decades to a phenomenon known as antibiotic resistance which is currently considered one of the principal threats to global public health by the World Health Organization. The aim to find alternative drugs has been demonstrated as a real challenge. Thanks to their biodiversity, insects represent the largest class of organisms in the animal kingdom. The humoral immune response includes the production of antimicrobial peptides (AMPs) that are released into the insect hemolymph after microbial infection. In this review, we have focused on insect immune responses, particularly on AMP characteristics, their mechanism of action and applications, especially in the biomedical field. Furthermore, we discuss the Toll, Imd, and JAK-STAT pathways that activate genes encoding for the expression of AMPs. Moreover, we focused on strategies to improve insect peptides stability against proteolytic susceptibility such as D-amino acid substitutions, N-terminus modification, cyclization and dimerization.