Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

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 worldwide1, 2. 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 tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. 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

Fabrication of Hydrophilic PDMS Surface using PVA Electrospun Nanofiber

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Au Hierarchical Nanostructure-Based Surface Modification of Microelectrodes for Improved Neural Signal Recording

Microelectrodes are widely used for neural signal analysis because they can record high-resolution signals. In general, the smaller the size of the microelectrode for obtaining a high-resolution signal, the higher the impedance and noise value of the electrodes. Therefore, to improve the signal-to-noise ratio (SNR) of neural signals, it is important to develop microelectrodes with low impedance and noise. In this research, an Au hierarchical nanostructure (AHN) was deposited to improve the electrochemical surface area (ECSA) of a microelectrode. Au nanostructures on different scales were deposited on the electrode surface in a hierarchical structure using an electrochemical deposition method. The AHN-modified microelectrode exhibited an average of 80% improvement in impedance compared to a bare microelectrode. Through electrochemical impedance spectroscopy analysis and impedance equivalent circuit modeling, the increase in the ECSA due to the AHN was confirmed. After evaluating the cell cytotoxicity of the AHN-modified microelectrode through an in vitro test, neural signals from rats were obtained in in vivo experiments. The AHN-modified microelectrode exhibited an approximate 9.79 dB improvement in SNR compared to the bare microelectrode. This surface modification technology is a post-treatment strategy used for existing fabricated electrodes, so it can be applied to microelectrode arrays and nerve electrodes made from various structures and materials.11Nsciescopu

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis.

New prophylactic and therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of extensively-drug resistant form of the disease. During the course of a high-content chemical screen, ImidazoPyridine Amides (IPA) were identified as a promising class of anti-tubercular agents. The optimized IPA compound Q203 inhibits the growth of multi- and extensively-drug resistant clinical isolates of M. tuberculosis in the low nanomolar range. Q203 was efficacious in vivo at a dose below 1mg/kg, making this compound one of the most potent discovered up to date. In addition, it shows pharmacokinetic and safety profiles compatible with once daily dosing. A reverse genetic approach identifies the ubiquinol cytochrome C reductase (QcrB, Rv2196) as the target of Q203. Mode of action studies revealed that Q203 inhibits the process of ATP synthesis in both replicating and hypoxic non-replicating M. tuberculosis. Altogether, our data indicates that Q203 is a promising clinical candidate for the treatment of tuberculosis

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

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.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe