A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant and Other High-Threat Pathogens.

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.

Dynamic compression locking system versus multiple cannulated compression screw for the treatment of femoral neck fractures: a comparative study.

Background: Femoral neck fractures are one of the problems in clinical treatment. The prognosis is uncertain. Currently, No internal fixation method is superior to other internal fixation methods in the treatment of femoral neck fractures.

A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure.

Antitubercular Triazines: Optimization and Intrabacterial Metabolism.

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring FH and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO and a des-nitro metabolite.

Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA.

We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA.

The clinical application of a novel method of internal fixation for femoral neck fractures-dynamic locking compression system.

Background: Femoral neck fractures are the commonly encountered injury in orthopedic practice and result in significant morbidity and mortality. Currently, how to treat femoral neck fractures safely and effectively is still a challenge. The objective of this study is to evaluate the efficiency of dynamic compression locking system for femoral neck fractures.

Diagnosis related group grouping study of senile cataract patients based on E-CHAID algorithm.

Aim: To figure out the contributed factors of the hospitalization expenses of senile cataract patients (HECP) and build up an area-specified senile cataract diagnosis related group (DRG) of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund.

Methods: The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis.

Addressing the Metabolic Stability of Antituberculars through Machine Learning.

We present the first prospective application of our mouse liver microsomal (MLM) stability Bayesian model. CD117, an antitubercular thienopyrimidine tool compound that suffers from metabolic instability (MLM < 1 min), was utilized to assess the predictive power of our new MLM stability model. The S-substituent was removed, a set of commercial reagents was utilized to construct a virtual library of 411 analogues, and our MLM stability model was applied to prioritize 13 analogues for synthesis and biological profiling.

Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins.

As a growing number of clinical isolates of are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of are synthesized by nonclassical transpeptidases, namely, the l,d-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen.

A Novel Small-Molecule Inhibitor of the Demethylmenaquinone Methyltransferase MenG Is Bactericidal to Both Growing and Nutritionally Deprived Persister Cells.

Active tuberculosis (TB) and latent infection both require lengthy treatments to achieve durable cures. This problem has partly been attributable to the existence of nonreplicating "persisters" that are difficult to kill using conventional anti-TB treatments. Compounds that target the respiratory pathway have the potential to kill both replicating and persistent and shorten TB treatment, as this pathway is essential in both metabolic states.

Non-classical transpeptidases yield insight into new antibacterials.

Bacterial survival requires an intact peptidoglycan layer, a three-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by D,D-transpeptidases, enzymes that are inhibited by the β-lactams, which constitute >50% of all antibacterials in clinical use. Here, we show that the carbapenem subclass of β-lactams are distinctly effective not only because they inhibit D,D-transpeptidases and are poor substrates for β-lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the L,D-transpeptidases, which generate the majority of linkages in the peptidoglycan of mycobacteria.

Combining Metabolite-Based Pharmacophores with Bayesian Machine Learning Models for Mycobacterium tuberculosis Drug Discovery.

Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome.

A Novel Allyl Transfer Coupled with a Grob Fragmentation.

A novel acid-promoted rearrangement is disclosed. In the previously unknown transformation, an allyl group migrated to an in situ formed carbocation stabilized by an electron-rich aryl or heteroaryl group, resulting in a stereoselective intramolecular Grob fragmentation. The outcome of the rearrangement observed with an array of substrates can be satisfactorily rationalized using a working hypothesis with the aid of a six-membered transition state similar to those proposed for the anionic oxy-Cope or oxonia-Cope rearrangements, but involving only one instead of two double bonds.

Evolution of a thienopyrimidine antitubercular relying on medicinal chemistry and metabolomics insights.

The metabolic instability of an antitubercular small molecule CD117 was addressed through iterative alteration of a key sulfide substituent and interrogation of the effect on growth inhibition of cultured . This process was informed by studies of the intramycobacterial metabolism of CD117 and its inactive carboxylic acid derivative. Isoxazole and thiazole demonstrated significant gains in mouse liver microsomal stability with slight losses in whole-cell activity.

A High Throughput Screening Assay for Anti-Mycobacterial Small Molecules Based on Adenylate Kinase Release as a Reporter of Cell Lysis.

Mycobacterium tuberculosis (Mtb) is well-established to be one of the most important bacterial pathogens for which new antimicrobial therapies are needed. Herein, we describe the development of a high throughput screening assay for the identification of molecules that are bactericidal against Mycobacteria. The assay utilizes the release of the intracellular enzyme adenylate kinase into the culture medium as a reporter of mycobacterial cell death.

A virtual screen discovers novel, fragment-sized inhibitors of Mycobacterium tuberculosis InhA.

Isoniazid (INH) is usually administered to treat latent Mycobacterium tuberculosis (Mtb) infections and is used in combination therapy to treat active tuberculosis (TB). Unfortunately, resistance to this drug is hampering its clinical effectiveness. INH is a prodrug that must be activated by Mtb catalase-peroxidase (KatG) before it can inhibit InhA (Mtb enoyl-acyl-carrier-protein reductase).

Electrodeposition of PbO and its in situ conversion to CH3NH3PbI3 for mesoscopic perovskite solar cells.

The perovskite CH3NH3PbI3 was prepared on a mesoscopic TiO2 film, starting from electrodepositing PbO, to iodination to PbI2, and then interdiffusion reaction with CH3NH3I. The as-prepared film was used as a light absorber for the perovskite solar cells, exhibiting a high PCE of 12.5% under standard AM 1.

[Clinical features of four atypical pediatric cases of endemic typhus with pneumonia].

Objective: To analyze clinical manifestations, treatment and prognosis of 4 cases with endemic typhus.

Method: The clinical data of four endemic typhus patients in prognosis were retrospectively analyzed. These four atypical cases of endemic typhus with pneumonia were treated in our department from October 2011 to March 2012.

Synthesis and absolute configuration of demethyl (C-11) cezomycin.

The synthesis of (-)-demethyl (C-11) cezomycin was achieved through an efficient route that features the use of a Kulinkovich reaction to couple two multifunctionality-containing fragments and a cascade of ring opening of cyclopropanol/1,5-hydrogen shift/desilylation-oxidation. The hidden yet undeniable problem of irreproducible specific rotation for this family of compounds was solved by sufficient acidification. The absolute configuration for the natural product was thus established as the mirror image of the synthetic sample.

Inhibition of allergic airway inflammation by antisense-induced blockade of STAT6 expression.

Background: The signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a pivotal role in asthma pathogenesis. Activation of STAT6 expression results in T helper cell type 2 (Th2) cell differentiation leading to Th2-mediated IgE production, development of allergic airway inflammation and hyperreactivity. Therefore, antagonizing the expression and/or the function of STAT6 could be used as a mode of therapy for allergic airway inflammation.

Mixed-valent manganese phosphonate clusters prepared under microwave-assisted and ambient conditions.

Mixed-valent manganese phosphonate clusters [Mn(II)(8)Mn(III)(2)O(2)(O(3)PC(10)H(7))(4)(C(6)H(5)CO(2))(10)(py)(4)(H(2)O)(2)] (1) and [Mn(II)(4)Mn(III)(9)O(4)(OH)(2)(O(3)PC(10)H(7))(10)(C(6)H(5)CO(2))(5)(py)(8)(H(2)O)(6)] (2) are reported. Compound 1 is the first example of manganese phosphonate clusters prepared through a microwave-assisted technique. While compound 2 is obtained under ambient condition, and exhibits slow magnetic relaxation behaviour at low temperature.