Mycobacterium tuberculosis with disrupted cdd gene.

Unlocking TB's Secrets: How Disrupting a Single Gene Could Revolutionize Treatment

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Rhea Morgan in Health & Wellness October 2026 • 4 min read.

"Scientists explore the impact of the 'cdd' gene in Mycobacterium tuberculosis, paving the way for novel therapies to combat this deadly disease."


Tuberculosis (TB), predominantly caused by Mycobacterium tuberculosis, remains a global health crisis. In 2015, the World Health Organization (WHO) reported 10.4 million new cases and 1.8 million deaths. While effective treatments exist, the rise of drug-resistant strains and the challenges of latent TB necessitate innovative therapeutic strategies.

Central to the search for new treatments is understanding the metabolic pathways that fuel the bacteria. Pyrimidine biosynthesis, crucial for creating essential building blocks of life, offers a promising target. Mycobacterium tuberculosis can synthesize pyrimidines de novo or scavenge them from their environment through the salvage pathway.

Among the key players in the pyrimidine salvage pathway is cytidine deaminase (MtCDA), an enzyme encoded by the cdd gene (Rv3315c). MtCDA recycles cytidine and deoxycytidine, essential for creating uridine and deoxyuridine. A new study investigates the impact of disrupting the cdd gene on Mycobacterium tuberculosis, assessing its role in growth, survival, and infection.

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Tracking TB Worldwide

The CDC publishes tuberculosis data on topics that help track progress toward elimination. Its provisional 2025 United States data report TB disease cases and rates by birth origin from 2010 to 2025, using reports submitted to the National Tuberculosis Surveillance System through February 12, 2026; annual rates are calculated per 100,000 persons. The WHO combines country-provided data with estimates of tuberculosis burden for its Global Tuberculosis Report, while TB Portals provides free, open access to tuberculosis datasets and research tools.

Treatment’s Persistent Challenges

Tuberculosis preventive therapy decreases the risk of developing TB disease and its associated morbidity and mortality, according to clinical standards for managing TB infection. However, a 2026 review reports that treatment length, drug toxicity, and the emergence of drug-resistant strains continue to challenge TB control despite effective therapies. The 2025 update from the Infectious Diseases Society of America likewise notes that treatment, particularly for drug-resistant TB, has historically involved prolonged courses of multiple medications and frequent adverse reactions.

What Happens When You Knockout the 'cdd' Gene?

Mycobacterium tuberculosis with disrupted cdd gene.

Researchers constructed a knockout strain of Mycobacterium tuberculosis in which the cdd gene was disabled. This was achieved through allelic replacement, a precise method of swapping out the original gene with a modified version. The successful deletion of the cdd gene was validated by assessing mRNA expression, confirming the absence of the gene product.

To ensure that knocking out cdd didn't unintentionally affect neighboring genes, the expression of deoA and add genes—located nearby on the chromosome—was also evaluated. Results indicated that the disruption of cdd did not have a polar effect, meaning it didn't disrupt the expression of these adjacent genes.

  • Confirmation of Disruption: mRNA analysis confirmed the absence of cdd gene expression in the knockout strain, validating the successful gene deletion.
  • No Polar Effects: The expression of neighboring genes (deoA and add) was unaffected, indicating a clean and specific knockout.
  • Protein Expression Analysis: MudPIT LC-MS/MS data provided insights into protein expression changes in the knockout strain.
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New Targets in TB Research

A PubMed review identifies the pyrimidine biosynthesis pathway as a potential source of TB drug targets because it is essential for mycobacteria and its enzymes differ from those found in humans. Recent research coverage also reflects efforts to characterize drug-resistant tuberculosis, including a study pooling data from 7,750 patients worldwide to define disease-severity phenotypes using clinical and treatment features. A 2025 Frontiers editorial describes current work spanning basic research, drug discovery, treatment, disease management, and how Mycobacterium tuberculosis adapts metabolically to different therapies.

Limits of Existing Strategies

The CDC lists a rifampin-based option lasting 18 weeks with three doses weekly for 54 doses, while cautioning its use in patients with HIV and/or cavitary disease. A study of a Mycobacterium tuberculosis cdd knockout reports that additional research under hypoxic and nutrient-limited conditions is needed because those conditions may better mimic the environment in which latent bacilli survive. Together, these sources underscore both regimen-specific clinical cautions and gaps in experimental evidence about latent infection.

Guidelines and Enzyme Function

The WHO’s Module 4 on treatment and care encompasses recommendations for drug-susceptible and drug-resistant TB, along with patient care and support. Separate structural and functional analyses of the Mycobacterium tuberculosis Rv3315c-encoded metal-dependent homotetrameric cytidine deaminase reported steady-state kinetic values for cytidine of Km = 1004 µM and kcat = 4.8 s−1. For 2′-deoxycytidine, the reported values were Km = 1059 µM and kcat = 3.5 s−1.

Using MudPIT LC-MS/MS, a sophisticated method for analyzing protein expression, researchers discovered an unexpected consequence: the expression of thymidine phosphorylase (MtTP), encoded by the deoA gene, was reduced in both the knockout and complemented strains. This suggests a possible interconnectedness between cdd and deoA at the translational level, where the efficiency of one gene's translation impacts the other.

What Does This Mean for TB Treatment?

While disrupting the cdd gene didn't prevent Mycobacterium tuberculosis from growing in standard lab conditions or within macrophages, it does shed light on the complex metabolic network that sustains the bacteria. Understanding the intricacies of pyrimidine metabolism and the roles of enzymes like MtCDA could reveal vulnerabilities that can be exploited for novel therapies, especially in the face of drug-resistant TB.

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Why New Interventions Matter

Tuberculosis infection caused by Mycobacterium tuberculosis remains a persistent global threat despite efforts to eradicate it, and HIV/AIDS is identified as one obstacle to complete eradication. A 2023 review reports that M. tuberculosis accounts for over ten million infections and over 1.5 million deaths every year, while emphasizing that infection creates changing, compositionally distinctive microenvironments through interactions with the immune system. Another review estimates 10.8 million new cases and 1.3 million deaths in 2023 and states that long treatment durations, drug toxicity, and drug-resistant strains continue to undermine global control.

Building Better TB Care

Future research should individualize treatment regimens, protect recent breakthroughs by preventing and identifying drug resistance, and expand affordable, patient-centered access to new options. A 2025 review describes drug-resistant M. tuberculosis as an ongoing challenge despite the BCG vaccine and available therapies, reinforcing the need for more effective vaccines and treatments. A systematic review published in 2025 aims to assess recent breakthroughs in TB drug development and their scientific value and global impact.

People at the Center

A global modelling analysis estimates that vaccination, community-wide screening, and prison screening programmes could prevent more than 10% of tuberculosis cases. WHO case studies published in 2024 present sixteen examples from countries across all regions and emphasize the essential role of community and civil society engagement in efforts to end TB. Clinical case-study resources also use real-life experiences of TB nurses to illustrate prevention, care, and TB nurse case management.

Pyrimidine salvage in the wider research landscape

A review proposes that hypoxia and nutrient deprivation during latent infection could make de novo synthesis less active and salvage more relevant for maintaining nucleotide pools. This is a proposed metabolic scenario, not a direct measurement of MtCDA activity in latent infection.[1]

Other pyrimidine nucleoside compounds have shown antimycobacterial activity in laboratory testing, including activity against drug-resistant strains in some reports. These compound results concern different molecules and do not demonstrate that disrupting cdd has the same effect.[2] [3] [4]

The reported activity is not universal: some soluble deoxyuridine derivatives lost antimicrobial activity entirely. This underscores that chemical changes within the same broad class can correspond to different outcomes.[4]

A GuaB2 inhibitor that killed replicating bacteria in vitro lacked activity in chronically infected mice, with several possible explanations reported. That example illustrates why activity in a laboratory growth setting does not by itself establish activity during chronic infection; it is not a result about cdd.[5]

A review of nucleotide metabolism frames metabolic pathways as possible sources for tuberculosis drug discovery, while focusing on DNA replication processes. It places metabolism in a discovery context without establishing a treatment effect for MtCDA.[6]

What evidence could clarify cdd's role

  • Does salvage become more important when hypoxia or nutrient deprivation attenuates de novo synthesis, and would that make MtCDA more consequential in those conditions?[1] [7]
  • Would changes to the salvage pathway translate into reduced bacterial activity during chronic infection, given that an inhibitor of a different metabolic target was active in vitro but not in chronically infected mice?[5]

Terms used in pyrimidine research

Salvage pathway
A route for obtaining pyrimidine nucleotides from preformed pyrimidine bases and nucleosides.[7]

Sources

  1. Targeting opportunities presented by the pyrimidine biosynthesis pathway in Mycobacterium tuberculosis: a brief review (pmc.ncbi.nlm.nih.gov)
  2. Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2'-'up' fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium i (pubmed.ncbi.nlm.nih.gov)
  3. Inhibition of Mycobacterium tuberculosis strains H37Rv and MDR MS-115 by a new set of C5 modified pyrimidine nucleosides. (pubmed.ncbi.nlm.nih.gov)
  4. Analogues of Pyrimidine Nucleosides as Mycobacteria Growth Inhibitors (pmc.ncbi.nlm.nih.gov)
  5. Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection (pmc.ncbi.nlm.nih.gov)
  6. Nucleotide Metabolism and DNA Replication. (doi.org)
  7. Construction of Mycobacterium tuberculosis cdd knockout and evaluation of invasion and growth in macrophages (pmc.ncbi.nlm.nih.gov)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

Everything You Need To Know

1

What is the role of the 'cdd' gene in Mycobacterium tuberculosis?

The 'cdd' gene encodes for cytidine deaminase (MtCDA) in Mycobacterium tuberculosis. MtCDA is an enzyme involved in the pyrimidine salvage pathway, which is crucial for recycling cytidine and deoxycytidine into uridine and deoxyuridine, essential building blocks for the bacteria. Disrupting the 'cdd' gene impacts the bacterium's ability to efficiently recycle these pyrimidines. This is significant because the pyrimidine salvage pathway is vital for the bacterium's survival, especially when de novo synthesis is limited. Inhibiting this pathway could weaken the bacterium, making it more susceptible to other treatments.

2

How did researchers study the 'cdd' gene's function in Mycobacterium tuberculosis?

Researchers created a Mycobacterium tuberculosis strain where the 'cdd' gene was disabled, or 'knocked out.' This was done using allelic replacement, a precise method to swap the original gene with a modified version. By knocking out the 'cdd' gene and studying the resulting strain, researchers can understand the gene's specific role in the bacterium's metabolism, growth, survival, and infection process. Understanding the function of individual genes like 'cdd' and how they contribute to the bacterium's survival mechanisms is essential for identifying potential drug targets.

3

What happens when the 'cdd' gene is knocked out in Mycobacterium tuberculosis?

When the 'cdd' gene is knocked out, the Mycobacterium tuberculosis strain can still grow in standard lab conditions and within macrophages. However, protein expression analysis revealed that the expression of thymidine phosphorylase (MtTP), encoded by the 'deoA' gene, was reduced in both the knockout and complemented strains. While the bacterium can still grow, these changes indicate an interconnectedness between 'cdd' and 'deoA' at the translational level, where the efficiency of one gene's translation impacts the other. Further research may uncover other metabolic disruptions that, when combined with other therapies, could weaken the bacteria.

4

How could disrupting the 'cdd' gene lead to new treatments for TB?

Disrupting the 'cdd' gene alone may not prevent Mycobacterium tuberculosis from growing, it reveals vulnerabilities in the bacteria's metabolic network, specifically pyrimidine metabolism. This suggests that targeting enzymes like MtCDA, which is encoded by the 'cdd' gene, could be a viable therapeutic strategy, especially in combination with other drugs. This is particularly relevant in the face of drug-resistant TB strains, where new treatment approaches are desperately needed. Further research into the pyrimidine salvage pathway could uncover more effective ways to combat TB.

5

What is MudPIT LC-MS/MS, and how was it used in this study?

MudPIT LC-MS/MS is a sophisticated method used for analyzing protein expression. In the context of the study, it allowed researchers to discover that knocking out the 'cdd' gene also affected the expression of thymidine phosphorylase (MtTP), encoded by the deoA gene. This revealed a possible interconnectedness between 'cdd' and 'deoA' at the translational level. The 'cdd' gene encodes for cytidine deaminase (MtCDA) which is part of the pyrimidine salvage pathway. Understanding how these genes interact and influence each other provides insights into the complex metabolic network of Mycobacterium tuberculosis and can help identify new targets for drug development.

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