Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug-drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilize conditional Mtb knockdown mutants of essential genes as an experimentally tractable surrogate for drug treatment, and probe the relationship between Mtb carbon metabolism and chemical-genetic interactions (CGI). We examined the anti-tubercular drugs isoniazid, rifampicin and moxifloxacin, and found that CGI are differentially responsive to the metabolic state, defining both environment independent and dependent synergies. Specifically, growth on the in vivo relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGI could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of novel chemical genetic environmental synergies that can be used to optimize drug-drug interactions as well as provide a framework for understanding in vitro correlates of in vivo efficacy.

Delivery of the bioactives to the brain is the utmost challenging task to cope with brain diseases. Brain is protected with blood brain barrier, blood-CSF barrier and efflux systems, which controls the entry of body as well as foreign compounds to access the brain cells. Only nutrients, which are essential for normal metabolism, can enter into the brain. In the shadow of this fact new strategies are being investigated to facilitate the entry of administered therapeutic compound into the brain. Active targeting is a evolving approach, which uses ligand and suitable carrier for the site-specific delivery and is being recently achieved by the use of nanocarriers. These nanocarriers are nanosized systems, which act as a cargo for the encapsulated drugs. At the same time, endo-or exogenous ligand can be attached to these nanocarriers to recognize specific receptors on brain capillary endothelium leading to delivery of drug in the vicinity of brain cells. Their potential is under immense investigation to increase the therapeutics outcome in the treatment of brain related problems. This review deals with the recent advances in nanocarriers based novel strategies for effective brain specific delivery.