The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.

A self-protective, reproducible electronic textile with desirable superlyophobicity, mechanical durability and high-sensitive performance for human-machine interaction.

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Background and Purpose: The role of the cartilage oligomeric matrix protein (COMP) in epithelial-mesenchymal transition (EMT) in tumor progression has been studied, but its exact regulatory mechanism remains unknown. Methods: The interaction between COMP and the actin-binding protein transgelin (TAGLN) was identified by interaction protein prediction and co-immunoprecipitation and verified through the stochastic optical reconstruction microscopy (STORM) and duolink experiments. Western blot and immunofluorescence analyses were conducted to detect the changes in EMT-related markers after COMP overexpression and knockdown. Molecular docking and Biacore of the interaction interface of COMP/TAGLN revealed that Chrysin directly targeted COMP. The promotion of COMP and the Chrysin inhibition of EMT were detected through the cell migration, invasion, apoptosis, and xenotransplantation of nude mice. Results: COMP interacts with TAGLN in EMT in colorectal cancer to regulate cytoskeletal remodeling and promote malignant progression. COMP is highly expressed in highly malignant colorectal cancer and positively correlated with TAGLN expression. COMP knockdown can inhibit colorectal cancer metastasis and invasion, whereas COMP overexpression promotes EMT in colorectal cancer. Through virtual screening of the protein interaction interface, Chrysin, a flavonoid compound extracted from Oroxylum indicum , was found to have the highest docking score to the COMP/TAGLN complex. Chrysin inhibited COMP, thereby preventing EMT and the malignant progression of colorectal cancer. Conclusions: This study illustrated the role of COMP in EMT and suggested that COMP/TAGLN may be a potential tumor therapeutic target. Chrysin exhibits obvious antitumor effects. This work provides a preliminary antitumor therapy to target COMP or its interaction protein to inhibit EMT.

As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2] cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These experiments clearly demonstrated that the geometry of the internal double bond and the presence of an electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75), ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured a novel domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core embodied in these alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to form the 13- and 8-membered rings leading to Z-72 and 74, the latter of which was quickly elaborated into ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially available starting materials with the longest linear sequence being 21 steps.

Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation.

BackgroundGastrointestinal stromal tumor (GIST) is a rare tumor of the small bowel, which can be difficult to diagnose and has a varied clinical outcome.PurposeThis is a retrospective review of the diagnosis, management, and clinical outcome of 32 patients diagnosed with primary small bowel GIST from a single center and a comparison of the findings with previously published cases.Patients and methodsRetrospective review of data from patient clinical records, endoscopic and imaging findings, surgical procedures, tumor histology and immunohistochemistry, and clinical outcome was conducted.ResultsData of 32 patients with a median age of 56 years including 50% men and women were reviewed. The majority (29/32) were symptomatic at presentation, with the main symptom being gastrointestinal bleeding (15/32). Imaging detection rates included ultrasound (0%), magnetic resonance imaging (0%), computed tomography (54.8%), computed tomography angiography (71.4%), and double-balloon enteroscopy (88.9%). The mean tumor diameter was 5.3 cm; 4 tumors were located in the duodenum, 21 in the jejunum, and 7 in the ileum. Based on the tumor size and mitotic index, 5 (15.6%), 15 (46.9%), 0 (0%), and 12 (37.5%) patients were classified into very low-risk, low-risk, intermediate-risk, and high-risk groups. Immunohistochemistry showed positive expression for CD117 (100%), CD34 (81.2%), DOG1 (93.8%), smooth muscle actin (37.5%), S100 (9.4%), and desmin (6.2%). Twenty-five patients (78.1%) were treated with open surgical tumor resection; seven patients (21.9%) underwent laparoscopic surgery. Postoperative complications that occurred in seven patients (21.9%) were resolved with conservative management. Four patients were treated with postoperative imatinib. At median follow-up of 30 months, two patients were died.ConclusionThe findings from this case series, combined with the findings from previously published cases, provide an update on the current status of the diagnosis and the therapeutic approaches that might lead to improvement in prognosis for patients who present with primary small bowel GIST.

A structure-guided drug design approach was used to optimize a novel series of aminobenzimidazoles that inhibit the essential ATPase activities of bacterial DNA gyrase and topoisomerase IV and that show potent activities against a variety of bacterial pathogens. Two such compounds, VRT-125853 and VRT-752586, were characterized for their target specificities and preferences in bacteria. In metabolite incorporation assays, VRT-125853 inhibited both DNA and RNA synthesis but had little effect on protein synthesis. Both compounds inhibited the maintenance of negative supercoils in plasmid DNA in Escherichia coli at the MIC. Sequencing of DNA corresponding to the GyrB and ParE ATP-binding regions in VRT-125853-and VRT-752586-resistant mutants revealed that their primary target in Staphylococcus aureus and Haemophilus influenzae was GyrB, whereas in Streptococcus pneumoniae it was ParE. In Enterococcus faecalis, the primary target of VRT-125853 was ParE, whereas for VRT-752586 it was GyrB. DNA transformation experiments with H. influenzae and S. aureus proved that the mutations observed in gyrB resulted in decreased susceptibilities to both compounds. Novobiocin resistance-conferring mutations in S. aureus, H. influenzae, and S. pneumoniae were found in gyrB, and these mutants showed little or no cross-resistance to VRT-125853 or VRT-752586 and vice versa. Furthermore, gyrB and parE double mutations increased the MICs of VRT-125853 and VRT-752586 significantly, providing evidence of dual targeting. Spontaneous frequencies of resistance to VRT-752586 were below detectable levels (<5.2 ؋ 10 ؊10 ) for wild-type E. faecalis but were significantly elevated for strains containing single and double target-based mutations, demonstrating that dual targeting confers low levels of resistance emergence and the maintenance of susceptibility in vitro.