Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is an ancient infectious disease that has plagued humankind for more than 70,000 years. It is estimated that one third of the human population harbours the pathogen in their bodies, with around 10 million new cases of tuberculosis a year.
Once described as the ‘Captain of all these men of death’, TB is still one of the leading causes of death worldwide today, according to a World Health Organisation report from 2020.
In 2019, almost half of global TB deaths occurred in Southeast Asia. The death rate from TB in Southeast Asia and around the world is worsened by the increasing resistance of the bacterium to antibiotics in recent years. Multidrug-resistant tuberculosis is now a major threat to the control of the disease.
To understand the metabolism of drug-resistant Mtb and develop drugs against it, NTU researchers Professor Gerhard Grüber from the School of Biological Sciences, Assoc Prof Roderick Wayland Bates from the School of Physical and Mathematical Sciences and Assoc Prof Kevin Pethe from the Lee Kong Chian School of Medicine started a transdisciplinary platform, called TOPNet, with the Experimental Drug Development Centre (EDDC), the national platform for drug discovery and development hosted at the Agency for Science, Technology and Research (A*STAR), and Prof Thomas Dick from the Center for Discovery and Innovation Hackensack Meridian Health (CDI).
TOPNet (short for Targeting Oxidative Phosphorylation Network) is funded by the National Research Foundation Singapore (NRF) and has been designated as a TB Excellence cluster.
Blocking energy generation to treat multidrug-resistant TB
TOPNet brings together expertise from the fields of Chemistry, Microbiology, Structural Biology, Drug Discovery, and Pharmacology to develop novel anti-tuberculosis drugs specifically targeting the oxidative phosphorylation pathway of Mtb that is essential for the bacteria to generate energy for growth.
“The enzymes in the oxidative phosphorylation pathway of Mtb have epitopes – unique regions that are specific to the bacteria – which are attractive targets for the design of drugs that inhibit or kill the pathogen but do not harm the host,” said Prof Grüber, lead Principal Investigator of TOPNet.
“By targeting the epitopes and disrupting the functions of these key enzymes, we hope to provide more effective solutions to treat multidrug-resistant TB.”
With NTU offering expertise in structural biology, mycobacterial physiology, bioenergetics, and drug discovery, and A*STAR’s EDDC providing high-throughput screening, chemical synthesis, and medicinal chemistry, the two partners have successfully determined the structures of regions in F1FO-ATP synthase, an enzyme in the Mtb oxidative phosphorylation pathway that produces adenosine triphosphate (ATP), the compound that provides energy to drive processes in living cells.
Using pharmacophore modelling to visualise the interactions of molecules with the enzymes as well as screening libraries of molecules and other medicinal chemistry approaches, the scientists have identified six novel compounds that inhibit F1FO-ATP synthase, opening the door to the development of potential drug candidates.
The researchers have also discovered a compound that inhibits cytochrome bd oxidase, another crucial enzyme that is required for energy generation in Mtb. When used together with the antituberculosis drug Telacebec, the molecule may shorten the duration of treatments for antibiotic-resistant TB.
In total, six technical disclosures for the compounds have been filed at NTUitive, NTU’s innovation and enterprise company. Two have been licensed out to industry. And more than 25 research publications have resulted from TOPNet.
“Drug discovery and development is a process that involves several phases, from fundamental research to clinical trials,” said Prof Grüber.
“This seamless tag-team of complementary expertise in TOPNet allows each partner to focus on what each does best. It has been critical to the success of this collaboration.”
Building on the success of TOPNet, NTU and EDDC are exploring the possibility of widening the collaboration to develop therapies for other superbugs.