National Research Foundation


Targeting oxidative phosphorylation for the rational development of sterilizing drug combination for drug-resistant tuberculosis (2017)

Our CoS team:
Lead PI: Prof. Dr. Gerhard Grüber (SBS)
Co-PIs: A/Prof. Roderick Bates (SPMS); A/Prof. Kevin Pethe (SBS/LKC)
Other team members:
Co-PIs: Prof. Alex Matter (Experimental Therapeutics Centre and D3, A*STAR), A/Prof. Thomas Dick (Yong Loo Lin School of Medicine, NUS)
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Gerhard Grüber
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Kevin Pethe
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Roderick Bates

Microbes have developed into specialized organisms, inhabiting nearly every ecosystem on today’s earth. This requires elaborate adaptation mechanisms to survive and thrive in these ecosystems. Adaptation of pathogenic bacteria such as Mycobacterium tuberculosis (Mtb) to its human host is possible due to their fascinating repertoire of genetic and biochemical mechanisms that allow them to adapt to their environments. During evolution Mtb employed a unique protein orchestra to synthesize the energy currency ATP (Adenosine triphosphate) in the pathway of oxidative phosphorylation, enabling the pathogen to survive in oxidative, and hypoxic environments inside granulomas. This energy producing pathway represents potential drug targets.
New antibiotics to fight drug resistant Tuberculosis bacteria are urgently needed. To develop new medicines against these superbugs we need to understand how the molecular machines that make up the tubercle bacillus work. We unraveled new mechanisms inside the critical energy generating machines, called cyt-bd oxidase and F-ATP synthase, identified (i) novel drug epitopes of these machines, (ii) novel compounds blocking energy generation and (iii) a novel epitope of the existing TB-drug bedaquiline. Our discoveries represent the missing step for the development of a rational sterilizing drug combination targeting oxidative phosphorylation for multi-drug and extensively drug resistant tuberculosis.
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Figure 1: Oxidative phosphorylation pathway in Mtb, and molecular targets for drug combination targeting the cyt-bd and F-ATP synthase.