New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

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ObjectiveSome researchers have raised concerns that pictorial health warning labels (HWLs) on cigarette packages may lead to message rejection and reduced effectiveness of HWL messages. This study aimed to determine how state reactance (i.e., negative affect due to perceived manipulation) in response to both pictorial and text-only HWLs is associated with other types of HWL responses and with subsequent cessation attempts.MethodsSurvey data were collected every 4 months between September 2013 and 2014 from online panels of adult smokers in Australia, Canada, Mexico, and the US were analyzed. Participants with at least one wave of follow-up were included in the analysis (n = 4,072 smokers; 7,459 observations). Surveys assessed psychological and behavioral responses to HWLs (i.e., attention to HWLs, cognitive elaboration of risks due to HWLs, avoiding HWLs, and forgoing cigarettes because of HWLs) and cessation attempts. Participants then viewed specific HWLs from their countries and were queried about affective state reactance. Logistic and linear Generalized Estimating Equation (GEE) models regressed each of the psychological and behavioral HWL responses on reactance, while controlling for socio-demographic and smoking-related variables. Logistic GEE models also regressed having attempted to quit by the subsequent survey on reactance, each of the psychological and behavioral HWL responses (analyzed separately), adjustment variables. Data from all countries were initially pooled, with interactions between country and reactance assessed; when interactions were statistically significant, country-stratified models were estimated.ResultsInteractions between country and reactance were found in all models that regressed psychological and behavioral HWL responses on study variables. In the US, stronger reactance was associated with more frequent reading of HWLs and thinking about health risks. Smokers from all four countries with stronger reactance reported greater likelihood of avoiding warnings and forgoing cigarettes due to warnings, although the association appeared stronger in the US. Both stronger HWLs responses and reactance were positively associated with subsequent cessation attempts, with no significant interaction between country and reactance.ConclusionsReactance towards HWLs does not appear to interfere with quitting, which is consistent with its being an indicator of concern, not a systematic effort to avoid HWL message engagement.

Negative emotions elicited by warnings encourage behavior change, promoting attention to warnings and behavioral responses that positively predict quit attempts.

We have developed a novel fluorogenic nanoprobe prepared from the assembly of CdSe/ZnS quantum dot (QD) and gold (Au) nanoparticles in which QD was conjugated with a specifically designed β-secretase (BACE1) substrate peptide, which was allowed to bind to the Ni-nitrilotriacetate (Ni-NTA) modified Au nanoparticles. This coordination-mediated binding of the QD with Au nanoparticles via Ni-NTA-histidine (His) interaction resulted in highly efficient quenching of QD fluorescence through a distance-dependent fluorescence resonance energy transfer (FRET) phenomenon. The prequenched QD-Au assembly recovered the fluorescence in the presence of the BACE1 enzyme after incubation in vitro. The high quenching efficiency of AuNP and robust QD fluorescence signal recovery upon BACE1 enzymatic digestion enabled us to visualize BACE1 activity in living cells, which further allowed us to generate the half maximal inhibitory concentration (IC(50)) values for BACE1 inhibitors in the cell-based assay utilizing a high throughput system (HTS). These results suggest the potential application of QD-AuNP assembly toward the HTS drug screening system as a robust and efficient probe to identify active molecules in BACE1-related diseases such as Alzheimer's disease.