Mycobacterium tuberculosis with disrupted cdd gene.

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

Rhea Morgan in Health & Wellness December 2025 • 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.

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.

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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Everything You Need To Know

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.

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.

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.

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.

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.