Introduction and Background of the Project

Introduction

Tuberculosis (TB) remains the world’s deadliest infectious disease, causing  approximately 1.5 million deaths and infecting nearly 10 million people each year. Current TB treatment requires multiple agents administered over several months and is often complicated by side effects and low patient compliance. The emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis, the bacterium that causes TB, further exacerbates this crisis, highlighting the urgent need for novel anti-TB agents.

Our primary goal is to discover new antimicrobial agents that target key metabolic pathways essential for the viability and pathogenesis of M. tuberculosis. The project team anticipates that targeting these pathways to develop antibiotics with novel mechanisms of action will improve clinical outcomes for TB patients and contribute to reducing the global incidence and mortality rates of TB.

Project objective

In the short term, this project aims to enhance TB antibiotic discovery by identifying secondary metabolites that specifically target this pathway in M. tuberculosis. By focusing on mechanisms absent in mammalian cells, the project team aims to identify secondary metabolites with selective antimicrobial activity and minimal side effects in humans. This selectivity is expected to improve patient experiences, compliance, and treatment outcomes. Early identification and testing of these compounds against purified proteins, M. tuberculosis cells, and human macrophage infection models will provide critical insights into their efficacy and potential as new therapeutic agents.

In the long term, our goal is to translate these research findings into clinical applications, offering new treatment options for TB patients worldwide. A key strength of this proposal is our established expertise and drug development pipeline, specifically in the TB context, which will be instrumental in advancing subsequent research and development phases.

Project design

Despite significant advances in understanding the metabolic features essential for M. tuberculosis, developing new antibiotics remains a major challenge. Enzyme inhibitors often exhibit limited activity against M. tuberculosis, and many bioactive compounds have unclear modes of action. To overcome these challenges, The project team will (a) identify secondary metabolites that specifically target key metabolic pathways in M. tuberculosis, and (b) test these metabolites against purified proteins and M. tuberculosis cells to assess their effects on bacterial growth and pathogenesis.

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

Our project aligns with global efforts to combat TB and other infectious diseases, particularly the World Health Organization's (WHO) End TB Strategy and the United Nations’ Sustainable Development Goals (SDGs). End TB Strategy aims to reduce TB incidence by 90% and TB-related deaths by 95% by 2035 (compared to 2015 levels), while the SDGs emphasize ensuring healthy lives and promoting well-being for everyone, with a specific target to end the epidemics of AIDS, TB, malaria, and neglected tropical diseases by 2030.

By contributing to the development of new TB treatments, our project directly supports these global initiatives, providing essential tools for controlling and eventually eradicating TB.

What sort of innovation are you bringing in your project?

This project incorporates several innovative approaches, including:

&nbsp

• Targeting an essential and unique bacterial pathway while avoiding interference with analogous system in humans, thereby minimizing off-target effects.

• Identifying drug-like molecules that naturally evolved to target specific proteins in competing microorganisms.

• Leveraging secondary metabolites, which offer distinct advantages over conventional drug screening approaches, including biological relevance, chemical diversity, and structural novelty.

Role and Responsibility of Each Partner

A/Prof. Bashiri’s team (The University of Auckland, New Zealand) will oversee overall project coordination and management. They will be responsible for protein production, assay development, and structural and microbial studies to elucidate the mode of action of the identified secondary metabolites.  

Prof. Abe’s team (The University of Tokyo, Japan) will identify secondary metabolites targeting specific metabolic pathways. These metabolites will then be produced for subsequent biochemical and microbiological studies by A/Prof. Bashiri.