In silico identification of potential inhibitors targeting Streptococcus mutans sortase A

Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans （S. mutans） utilizes sortase A （SrtA） to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity （ADMET） properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic In addition, the carbonyl of these compounds can have a strategy for microbial infection disease therapy. parameters, were potential inhibitors to impede the catalysis of SrtA. key role in the inhibition mechanism. These findings can provide a new

Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors

a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Epidemiological and antibiotic resistant study on extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in Zhejiang Province

To investigate the epidemiological status of extended spectrum β lactamase (ESBL) producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) and the drug resistance profiles of such organisms Methods A total of 282 clinical isolates of E coli and 180 of K pneumoniae were collected from different districts of Zhejiang Province Inhibitor potentiated broth dilution tests were performed for detecting extended spectrum β lactamases Etests were performed to detect the drug resistance of these strains against nine commonly used antibiotics Results The prevalence of extended spectrum β lactamases in E coli and K pneumoniae was 34 0% and 38 3%, respectively The average prevalence of extended spectrum β lactamases in E coli and K pneumoniae was 35 7% The resistance prevalence of extended spectrum β lactamase producing strains to ceftazidime and cefotaxime was 40% and 26% respectively, so were those to cefepime, cefoxitin, piperacillin tazobactam, cefoperazone sulbactam, amikacin and ciprofloxacin All these strains were sensitive to imipenem Conclusion The results in this study showed that the prevalence of extended spectrum β lactamases was high, while extended spectrum β lactamase producing strains were resistant to most antimicrobial agents except imipenem