Chemigenomic Drug Discovery for Tuberculosis
Abstract
We propose to leverage a new generation of genetic and chemical approaches to develop novel therapeutics for tuberculosis, thus addressing the Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area “Tuberculosis.” Tuberculosis (TB) is the leading cause of infectious disease death in the world, killing more than a million people each year. The primary reasons for this enormous toll are twofold. Treatment for TB is demanding, requiring the patient to take multiple antibiotics for 6 months. Symptoms often improve rapidly, which leads to decreasing compliance with the long course of drugs -- and non-compliance is associated with increased risk of relapse and, potentially, development of drug-resistant disease. Thus, while the drugs themselves are inexpensive, maintaining the infrastructure to ensure a steady supply of antibiotics and ensure that patients take all of their doses (by direct observation) is quite expensive and often beyond the means of the health systems in areas where TB is endemic. Secondly, the incidence of drug-resistant TB is rising worldwide, and drug-resistant disease is very difficult, and occasionally impossible, to treat. At best, treatment of multidrug-resistant (MDR) TB requires a considerably longer course and is associated with an enormous increase in the number and severity of side effects. And, since these cases are transmissible, even relatively low-risk patients can develop infection and disease. Thus, there is a substantial need for better therapy that effectively treats both drug-sensitive and drug-resistant disease with a shortened treatment course. We aim to use a combination of new approaches that will enable us to rapidly identify new drugs that could be used to treat all types of TB infection and that could shorten therapy. We will take advantage of unique chemical and genetic tools and the expertise of participants in TB, structural biology, pharmacology, and drug discovery and development. We will identify novel targets in the TB bacterium that, when inhibited, lead directly to bacterial death or synergize to increase the effectiveness of existing antibiotics. We will then purify these targets and use them to identify small molecules that inhibit their function. We will characterize these target-compound pairs, from structural binding studies to efficacy of bacterial killing both in vitro and in vivo, which can then serve as starting points for developing new treatments for TB. If successful, these agents could transform TB therapy and these approaches could serve as a template for new drug development for other drug-resistant infections.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710692
Entities
People
- Eric Rubin
Organizations
- President and Fellows of Harvard College
- United States Army