We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.

Tin sulfide-based materials can exist in many forms, ranging from discrete molecular species, to 1D chains, 2D dense and porous sheets and 3D open frameworks. The local coordination geometry around a tin center may vary from trigonal pyramidal, to tetrahedral, trigonal bipyramidal and octahedral, and around sulfur from terminal, v-shaped to trigonal pyramidal. The oxidation state may take +2 and +4 for tin and −2, −1, 0 for sulfur. The tin sulfide chemistry is further enriched by the catenation ability of sulfur. In addition, other elements (metal and non-metal) can be incorporated into the tin sulfide structures to yield ternary and quaternary materials. More importantly, using the recent developed 'soft chemistry' synthetic approach, various novel porous tin (poly)sulfide materials have emerged that display interesting optical, electrical and adsorption properties. Representative tin sulfide materials will be presented and discussed in this review to demonstrate the development of tin sulfide chemistry in the last three decades. monomeric8 (SnS 4)4−, dimeric9,10 (Sn 2 S 6 )4− and (Sn 2 S 7 )6−

Persistent endoplasmic reticulum (ER) stress in neurons is associated with activation of inflammatory cells and subsequent neuroinflammation following traumatic brain injury (TBI); however, the underlying mechanism remains elusive. We found that induction of neuronal-ER stress, which was mostly characterized by an increase in phosphorylation of a protein kinase R-like ER kinase (PERK) leads to release of excess interferon (IFN)␤ due to atypical activation of the neuronal-STING signaling pathway. IFN␤ enforced activation and polarization of the primary microglial cells to inflammatory M1 phenotype with the secretion of a proinflammatory chemokine CXCL10 due to activation of STAT1 signaling. The secreted CXCL10, in turn, stimulated the T-cell infiltration by serving as the ligand and chemoattractant for CXCR3 ϩ T-helper 1 (Th1) cells. The activation of microglial cells and infiltration of Th1 cells resulted in white matter injury, characterized by impaired myelin basic protein and neurofilament NF200, the reduced thickness of corpus callosum and external capsule, and decline of mature oligodendrocytes and oligodendrocyte precursor cells. Intranasal delivery of CXCL10 siRNA blocked Th1 infiltration but did not fully rescue microglial activation and white matter injury after TBI. However, impeding PERK-phosphorylation through the administration of GSK2656157 abrogated neuronal induction of IFN␤, switched microglial polarization to M2 phenotype, prevented Th1 infiltration, and increased Th2 and Treg levels. These events ultimately attenuated the white matter injury and improved anxiety and depressive-like behavior following TBI.