A Chemical Genomic Approach to Define Antitubercular Mechanism of Action
Abstract
Despite the availability of tuberculocidal antibiotics since the 1940s, over one-quarter of the world remains infected and approximately 1.6 million people die of TB every year. Public health efforts to restrain the TB pandemic are limited by the inadequacies of current TB chemotherapy. TB treatment is complicated, requiring a minimum of two months of four medications followed by an additional four months of two medications. Completing this protracted treatment regime is critical – failure to finish therapy is associated with TB relapse as well as the emergence of drug-resistant TB. However, TB generally responds to treatment within weeks of starting therapy and patients start to feel better. Thus, patients have little motivation to continue through the long course of chemotherapy, particularly when they develop adverse side effects due to drug toxicity. Because of this, the World Health Organization recommends that each dose of medication be taken under direct observation to ensure patient compliance – so-called directly observed therapy (DOT) – leading to a set of guidelines followed by much of the world including the United States military. This protocol is expensive, logistically complex, and is a significant burden on the public health infrastructure, particularly for many of the developing countries where the rates of TB are highest. Furthermore, current therapy is only successful for TB caused by bacteria that are sensitive to the standard drug regimen. Drug-resistant bacteria are far more difficult to treat. Current regimens to treat drug-resistant TB are long (two years of chemotherapy or longer), toxic and, often, unsuccessful. With an estimate of 560,000 new cases of drug-resistant TB in 2018, a substantial part of the burden of TB disease is poorly or not addressed by current therapy. For these reasons, a central goal of the TB research community is to identify and characterize a suite of new antituberculars capable of improving therapy. The deficiencies of standard Mtb genetic tools have limited the pace and scope of new TB drug discovery. This proposal seeks to develop an innovative CRISPR-based genetic platform to define the mechanism of action (MOA) by which novel antibiotics kill Mtb. This represents an entirely new approach in the field, with great potential to provide new insights, paradigms, research directions, and technologies. This work represents a substantial departure from the status quo of both TB genetics and drug discovery, and thus innovates from a biological, therapeutic, and technological standpoint. This proposal will develop a transformative new approach for the field, as well as lay the foundation for future studies to enable high-throughput MOA prediction of poorly characterized but proven whole-cell active antituberculars, and thereby accelerate TB drug discovery and development. The short-term impact of this research program will be to: (1) produce an innovative technology to identify and characterize new antituberculars and (2) provide critical information for the advancement of three poorly understood lead anti-TB antibiotics. This 2-year proposal will generate the preliminary data to lay the foundation for more expansive, long-term future research projects. The long-term impact of this program will be to produce a scalable, generally applicable platform that can classify and prioritize hit and lead anti-TB compounds. Importantly, this project develops an approach to discover and prioritize anti-TB drugs with new targets and new mechanisms of action – a critical requirement for the development of new therapies to treat drug-resistant TB. The long-term goal of this research is to promote the preclinical development of new drugs that could shorten the course of treatment for both drug-sensitive and drug-resistant TB. New TB therapies, particular those capable of treating drug-resistant TB, would provide tremendous dual-use benefits to both our military personnel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010163
Entities
People
- Jeremy Rock
Organizations
- The Rockefeller University
- United States Army