Introduction and Background of the Project

Introduction

Most TB drugs currently in use were discovered 40-50 years ago and little has changed over this period.  To treat people with drug-sensitive TB, it takes on average 6 months of treatment with multiple drugs a day.  In the case of drug-resistant TB, the situation is much worse, often requiring continued medication for at least 18 months and sometimes less effective and toxic drugs. The treatment success rate for multidrug-resistant TB is currently estimated at 54%. Therefore, new TB drugs are urgently needed to shorten the treatment duration and to combat drug-resistant strains of Mycobacterium tuberculosis (M tb), the causative agent of TB. 

Project objective

Identification of lead compounds that can result in effective new tuberculosis drugs including treatment shortening and cure for both drug-sensitive and drug-resistant TB.  

Project design

This project was a result of screening effort among Daiichi Sankyo RD Novare, TB Alliance, and the Research Institute of Tuberculosis (Japan Anti-tuberculosis Association) which began with a support from the GHIT Fund. Daiichi Sankyo RD Novare's original natural product library created from microorganisms such as actinomycetes and fungi, consisting of 30,000 extracts and 600 purified natural compounds. The Research Institute of Tuberculosis evaluated bactericidal activity against TB using the natural product library. Through close cooperation of these three research institutes, a group of hit compounds were identified and the structures of the active components were determined.  The active components were further studied for their biological properties and a research plan was developed to generate additional fermentation products for structural modifications and biological evaluations. The medicinal chemistry program was developed by consultation between Daiichi Sankyo RD Novare and TB Alliance.

How can your partnership (project) address global health challenges?

TB causes approximately 1.6 million deaths per year globally. One of the challenges of current TB care is duration of therapy and lack of new treatments that are effective against drug-resistant strains.  This collaboration between Daiichi Sankyo RD Novare and TB Alliance is uniquely poised to deliver novel drug candidates to combat TB. TB Alliance is a product development partnership (PDP), a type of organization that focuses R&D activities in the area of health need where there is a lack of private sector investment due to insufficient potential profits. This collaboration allows for the sharing of know-how found in Japanese companies' exceptional natural chemistry, as well as the vast network of TB Alliance partners, with academic researchers throughout the world. It is designed to maximize the impact of research in TB, a severely under-resourced therapeutic area. The objective of this collaboration is to provide drug leads that can be further optimized toward preclinical and eventually clinical trials. 

What sort of innovation are you bringing in your project?

A library of natural products from which original hit compounds are generated from screening against TB is used from nearly 60,000 strains of microorganisms collected over 30 years from all over Japan. This natural product library is the original library of Daiichi Sankyo RD Novare and has not been screened against TB after the current form of the natural product library was constructed. The use of natural products as starting points and utilization of the cumulative knowledge of natural product chemistry and synthetic expertise provide a unique opportunity to discover novel treatments for TB. 

Role and Responsibility of Each Partner

In this research program, Daiichi Sankyo RD Novare will synthesize and provide derivative starting compounds required for the development of derivatives by fermentation and purification of the producing microorganisms. TB Alliance and Daiichi Sankyo RD Novare will jointly determine new analogues to be prepared from the fermentation products and the semi-syntheses will be carried out by contract research organizations (CROs). The pharmacological activity of the synthesized compound against TB is evaluated at the University of Illinois. The result expected for this collaborative research is to identify lead compounds within 24 months.