Preclinical Validation of a Novel Drug Lead to Treat Tuberculosis
Abstract
Relevance of the Project to Topic Area: This project relates to the Topic Area of Tuberculosis addressing the Area of Encouragement: Research to understand, diagnose, or treat multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis through the development of a new class of tuberculosis antibiotics. Tuberculosis (TB) is an infectious disease that affects millions of people globally. While TB is, in principle, curable through long-term treatments with a combination of antibiotics, 1.8 million people die of this disease every year worldwide. The reasons are varied, but include poor access to diagnosis and treatment, particularly in developing countries, significant comorbidity with HIV, multidrug resistance (MDR), and delays in bringing new TB antibiotics to the clinic. TB disease that is resistant to one or multiple TB antibiotics is a major concern worldwide, as it limits the treatment options for patients, requires use of TB drugs that have toxic side effects, extends the treatment from usually 6-9 months for drug-sensitive TB up to 2 years for MDR TB. Moreover, treatment of MDR TB has a higher chance to fail and not cure the patient, and death is more likely to occur in patients with MDR TB compared to those with drug-sensitive TB. Over the next 10 years, it is estimated that it will cost the world’s economies USD 1-3 trillion to deal with TB. Notwithstanding past success, modern TB treatment relies on antibiotics that are slow to affect a cure, complicated to administer, and exhibit toxic side effects. There are promising new TB antibiotics in the pipeline; however, given the scale of the challenge, there is an urgent need to invest in the further discovery and development of improved TB antibiotics that enable shorter treatment times and are not compromised by current antibiotic resistance mechanisms. In this project, we will chemically refine and biologically characterize a novel chemical compound class, the wollamides, which we originally isolated from a soil bacterium found at a remote Australian cattle station. Wollamides kill TB bacteria, are not toxic to human cells, and impair the ability of TB bacteria to survive in the cells it infects inside the human body. Building on these discoveries and the proven capabilities of our multidisciplinary team, this project seeks to advance these novel wollamides into a new class of antibiotics to treat TB. To do this, we will: (1) Optimize the chemical structure of the wollamides for potency against TB bacteria. (2) Determine whether wollamides enhance or impair the effects of currently used TB antibiotics, are active against TB bacteria that are isolated from TB patients, and are effective against multidrug-resistant TB. (3) Characterize the effects of wollamides on TB bacteria to identify how wollamides affect TB bacteria and how TB bacteria might develop resistance against wollamides. This will direct wollamide optimization and may also aid in the discovery of new improved drugs that act on TB bacteria in a way similar to wollamides. (4) Determine the anti-TB activity of optimized wollamides in the infected individual using a preclinical TB infection model. Impact: Without urgent investment into the development of better TB treatments that are effective against MDR TB, the world faces a future with fewer, less effective TB antibiotics, leading to increased mortality and social and economic distress. This project will optimize a promising new class of natural product-inspired chemicals, the wollamides, for efficacy against TB bacteria and provide in-depth molecular characterization of wollamide resistance and effects on TB bacteria. This knowledge is essential to advance preclinical and clinical testing of the wollamides and could be harnessed for the identification of new chemical structures that could be developed into treatments for TB. The outcomes of this project have the potential to help develop safer, faster acting, and m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810636
Entities
People
- Antje Blumenthal
Organizations
- United States Army
- University of Queensland