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

Architecture of a nascent viral fusion pore

Enveloped viruses use specialized protein machinery to fuse the viral membrane with that of the host cell during cell invasion. In influenza virus, hundreds of copies of the haemagglutinin (HA) fusion glycoprotein project from the virus surface. Despite intensive study of HA and its fusion activity, the protein's modus operandi in manipulating viral and target membranes to catalyse their fusion is poorly understood. Here, the three-dimensional architecture of influenza virus–liposome complexes at pH 5.5 was investigated by electron cryo-tomography. Tomographic reconstructions show that early stages of membrane remodeling take place in a target membrane-centric manner, progressing from punctate dimples, to the formation of a pinched liposomal funnel that may impinge on the apparently unperturbed viral envelope. The results suggest that the M1 matrix layer serves as an endoskeleton for the virus and a foundation for HA during membrane fusion. Fluorescence spectroscopy monitoring fusion between liposomes and virions shows that leakage of liposome contents takes place more rapidly than lipid mixing at pH 5.5. The relation of ‘leaky' fusion to the observed prefusion structures is discussed

Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a murine model of tuberculosis

10.1371/journal.pone.0105222PLoS ONE98e10522

Band bending at heterovalent interfaces Hard X ray photoelectron spectroscopy of GaP Si 001 heterostructures

GaP is a preferred candidate for the transition between Si and heterogeneous III V epilayers as it is nearly lattice matched to Si. Here, we scrutinize the atomic structure and electronic properties of GaP Si 0 0 1 heterointerfaces utilizing hard X ray photoelectron spectroscopy HAXPES . GaP 0 0 1 epitaxial films with thicknesses between 4 and 50 nm are prepared by metalorganic vapor phase epitaxy on either predominantly single domain SD or two domain TD Si 0 0 1 surfaces. The antiphase domain content in the GaP films is in situ controlled, employing reflection anisotropy spectroscopy. Via the analysis of core level photoelectron intensities, we reveal core level shifts of the P 2p and Si 2p peaks near the interface as well as core level shifts in the Ga 3d peaks near the surface. We suggest an Inter Diffused Layer IDL model of the GaP Si 0 0 1 interfacial structure with Sisingle bondP bonds at the heterointerface and residual P atoms in the Si substrate. Using a newly developed Parametrized Polynomial Function PPF approach, we derive a non monotonic band bending profile in the heterostructures, correct experimental valence band offsets implying interfacial electronic barriers, and determine valence band discontinuities of amp; 9651;EV 1.1 0.2 eV SD samples and amp; 9651;EV 0.8 0.2 eV TD samples at GaP Si 0 0 1 interface

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease