Small-Molecule Inhibitors of the Type III Secretion System

Drug-resistant pathogens have presented increasing challenges to the discovery and development of new antibacterial agents. The type III secretion system (T3SS), existing in bacterial chromosomes or plasmids, is one of the most complicated protein secretion systems. T3SSs of animal and plant pathogens possess many highly conserved main structural components comprised of about 20 proteins. Many Gram-negative bacteria carry T3SS as a major virulence determinant, and using the T3SS, the bacteria secrete and inject effector proteins into target host cells, triggering disease symptoms. Therefore, T3SS has emerged as an attractive target for antimicrobial therapeutics. In recent years, many T3SS-targeting small-molecule inhibitors have been discovered; these inhibitors prevent the bacteria from injecting effector proteins and from causing pathophysiology in host cells. Targeting the virulence of Gram-negative pathogens, rather than their survival, is an innovative and promising approach that may greatly reduce selection pressures on pathogens to develop drug-resistant mutations. This article summarizes recent progress in the search for promising small-molecule T3SS inhibitors that target the secretion and translocation of bacterial effector proteins

Alternate Synthesis of HSP90 Inhibitor AT13387

<div><p></p><p>AT13387 is a novel HSP90 inhibitor, and it is currently used in clinical trials for the treatment of refractory gastrointestinal stromal tumors (GIST). In this article, two synthetic routes are described for synthesizing the title compound via [2 + 2 + 2] cycloaddition of dipropargylamine derivatives and propargyl alcohol as a key step. The alternate synthetic methods are economical and suitable for multigram-scale preparation of AT13387 and the related isoindoline derivatives.</p> </div

Diminished treatment response in relapsed versus first-episode schizophrenia as revealed by a panel of blood-based biomarkers: A combined cross-sectional and longitudinal study

There is a paucity of biomarkers for the prediction of treatment response in schizophrenia. In this study, we aimed to investigate whether diminished antipsychotic treatment response in relapsed versus first-episode schizophrenia can be revealed and predicted by a panel of blood-based biomarkers. A cross-sectional cohort consisting of 655 schizophrenia patients at different episodes and 606 healthy controls, and a longitudinal cohort including 52 first-episode antipsychotic-naive schizophrenia patients treated with the same antipsychotic drugs during the 5-year follow-up of their first three episodes were enrolled. Plasma biomarker changes and symptom improvement were compared between the drug-free phase of psychosis onset and after 4 weeks of atypical antipsychotic drug (AAPD) treatment. In response to treatment, the extent of changes in the biomarkers of bioenergetic, purinergic, phospholipid and neurosteroid metabolisms dwindled down as number of episode and illness duration increased in relapsed schizophrenia. The changes of creatine, inosine, progesterone, allopreg-nanolone, cortisol and PE(16:0/22:6) were significantly correlated with the improvement of symptomatology. Inosine and progesterone at baseline were shown to be strong predictive biomarkers of treatment response. The results suggest that AAPD treatment response is diminished in the context of relapse, and our findings open new avenues for understanding the pathophysiology of treatment-resistance schizophrenia