Microscopic view of Mycobacterium tuberculosis adapting to hypoxia, with metabolic pathways and drug molecule.

Starve a Cold, Starve TB? How a New Metabolic Strategy Could Help Conquer Tuberculosis

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Kai Mendoza in Health & Wellness August 2025 • 5 min read.

"Researchers discover a key metabolic adaptation in Mycobacterium tuberculosis that could lead to new, more effective therapies for this persistent disease."


Tuberculosis (TB), a disease that has plagued humanity for centuries, remains a global health crisis. Its resilience stems from the ability of the causative agent, Mycobacterium tuberculosis (Mtb), to persist in the human body for years, often in a dormant, non-replicating state that is remarkably resistant to antibiotics. This latent form of TB affects over a billion people worldwide, serving as a vast reservoir for potential reactivation and transmission.

Current TB treatment regimens are lengthy and complex, requiring the administration of multiple drugs for at least six months. This prolonged course not only poses logistical challenges but also contributes to the rise of drug-resistant strains, further complicating the fight against this deadly disease. Finding ways to shorten treatment duration and improve drug efficacy is therefore a critical priority.

Now, a groundbreaking study published in Cell Chemical Biology sheds new light on how Mycobacterium tuberculosis adapts to survive in low-oxygen environments, a state often encountered within the human host. By identifying key metabolic pathways essential for the survival of these non-replicating bacteria, the researchers have uncovered a potential new strategy for developing more effective TB therapies.

Unmasking the Metabolic Secrets of Dormant TB

Microscopic view of Mycobacterium tuberculosis adapting to hypoxia, with metabolic pathways and drug molecule.

The research team, led by Christopher M. Sassetti at the University of Massachusetts Medical School, employed a comprehensive genetic screening approach to identify genes essential for the survival of Mtb under hypoxic (low-oxygen) conditions. They created a highly saturated library of Mtb mutants and subjected them to prolonged hypoxic stress, tracking which mutants thrived and which ones faltered. This "transposon sequencing" (TN-seq) strategy allowed them to pinpoint the genes crucial for adapting to and surviving in a low-oxygen environment.

The screen revealed a surprising key player: a protein acetyltransferase called Mt-Pat (Rv0998). This enzyme, previously known to be involved in regulating carbon metabolism, was found to be essential for Mtb's survival under hypoxic stress. Further investigation revealed that Mt-Pat promotes a shift in the bacteria's metabolism, favoring reductive tricarboxylic acid (TCA) reactions. These reactions, which essentially run the TCA cycle in reverse, help the bacteria maintain their redox balance – a critical factor for survival in the absence of oxygen.

  • Reductive TCA Reactions: Under hypoxic conditions, Mtb relies on reductive TCA reactions to regenerate NAD+, a crucial molecule for energy production and maintaining cellular function.
  • Malate Dehydrogenase (Mdh): This enzyme is a key component of the reductive TCA pathway, facilitating the conversion of malate to succinate.
  • Mt-Pat's Role: The protein acetyltransferase Mt-Pat promotes reductive TCA reactions in hypoxia.
The researchers discovered that Mt-Pat influences the flux of carbon through the TCA cycle, diverting it away from oxidative reactions and towards reductive ones. This metabolic shift is crucial for regenerating NAD+ and maintaining the bacteria's energy supply in the absence of oxygen. Further experiments confirmed the importance of malate dehydrogenase (Mdh), a key enzyme in the reductive TCA pathway. When Mdh was inhibited, either genetically or chemically, Mtb rapidly lost viability under hypoxic conditions and during infection in mice.

A New Hope for TB Treatment?

These findings offer a promising new avenue for developing more effective TB therapies. By targeting the Mtb's metabolic adaptations to hypoxia, specifically the reductive TCA pathway and the enzyme Mdh, researchers hope to develop drugs that can kill dormant bacteria and shorten treatment times. The study also revealed structural differences between human and mycobacterial Mdh, suggesting that it may be possible to design drugs that selectively inhibit the bacterial enzyme without harming the host.

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This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.chembiol.2018.09.009, Alternate LINK

Title: A Lysine Acetyltransferase Contributes To The Metabolic Adaptation To Hypoxia In Mycobacterium Tuberculosis

Subject: Clinical Biochemistry

Journal: Cell Chemical Biology

Publisher: Elsevier BV

Authors: Emily S.C. Rittershaus, Seung-Hun Baek, Inna V. Krieger, Samantha J. Nelson, Yu-Shan Cheng, Subhalaxmi Nambi, Richard E. Baker, John D. Leszyk, Scott A. Shaffer, James C. Sacchettini, Christopher M. Sassetti

Published: 2018-12-01

Everything You Need To Know

1

How does *Mycobacterium tuberculosis* adapt its metabolism to survive in low-oxygen environments, and what key processes are involved?

The study revealed that under low-oxygen conditions, *Mycobacterium tuberculosis* (Mtb) relies on reductive TCA reactions to regenerate NAD+. This process is crucial for maintaining energy production and cellular function in the absence of oxygen. Key to this process is the enzyme malate dehydrogenase (Mdh), which facilitates the conversion of malate to succinate, and the protein acetyltransferase Mt-Pat, which promotes reductive TCA reactions.

2

What is the role of Mt-Pat (Rv0998) in the survival of *Mycobacterium tuberculosis* under hypoxic conditions, and how does it influence metabolic pathways?

Mt-Pat (Rv0998) is a protein acetyltransferase that plays a vital role in the survival of *Mycobacterium tuberculosis* under hypoxic stress. It promotes a shift in the bacteria's metabolism, favoring reductive tricarboxylic acid (TCA) reactions. This shift is essential for maintaining redox balance, which is critical for survival in low-oxygen environments. Mt-Pat influences the flux of carbon through the TCA cycle, diverting it away from oxidative reactions and towards reductive ones, ensuring the bacteria's energy supply is maintained.

3

What are the potential therapeutic implications of targeting the reductive TCA pathway and malate dehydrogenase (Mdh) in *Mycobacterium tuberculosis*, and how could this improve TB treatment?

Researchers hope that by targeting *Mycobacterium tuberculosis*' metabolic adaptations to hypoxia, specifically the reductive TCA pathway and enzymes like malate dehydrogenase (Mdh), they can develop drugs that effectively kill dormant bacteria. These drugs could shorten treatment times for tuberculosis and improve overall treatment outcomes. Furthermore, structural differences between human and mycobacterial Mdh offer the potential to design drugs that selectively inhibit the bacterial enzyme without harming the host.

4

What challenges do current tuberculosis treatment regimens pose, and how might understanding *Mycobacterium tuberculosis*' metabolic adaptations help overcome these challenges?

Current tuberculosis (TB) treatment regimens are lengthy and complex, requiring the administration of multiple drugs for at least six months. This prolonged course not only poses logistical challenges but also contributes to the rise of drug-resistant strains. The latent form of TB, affecting over a billion people worldwide, serves as a reservoir for potential reactivation and transmission. The discovery of *Mycobacterium tuberculosis*' metabolic adaptations to hypoxia offers hope for shortening treatment duration and improving drug efficacy.

5

Can you explain the transposon sequencing (TN-seq) strategy used to identify genes essential for the survival of *Mycobacterium tuberculosis* under hypoxic conditions?

The transposon sequencing (TN-seq) strategy involves creating a highly saturated library of *Mycobacterium tuberculosis* mutants and subjecting them to prolonged hypoxic stress. By tracking which mutants thrived and which ones faltered, researchers can pinpoint the genes crucial for adapting to and surviving in a low-oxygen environment. This genetic screening approach allowed the research team to identify genes essential for the survival of Mtb under hypoxic conditions, including the discovery of the protein acetyltransferase Mt-Pat's role.

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