New Therapeutic Approaches for Tuberculosis

Technology Overview

Dr. Chrisoph Grundner

Bacterial phosphosignaling pathways convert extracellular information, such as nutrient availability or the presence of antibiotics, into intracellular responses. A key reaction in phosphosignaling is reversible protein phosphorylation. The addition of phosphate groups to proteins by kinases and removal of this modification by phosphatases is a common mechanism for controlling protein activity.

Infectious disease expert Christoph Grundner, PhD, investigates phosphosignaling pathways and kinases in Mycobacterium tuberculosis (Mtb). This bacterium causes tuberculosis (TB), which kills approximately 1.2 million people worldwide every year. Treating TB is difficult, in part because of widespread resistance to current antibiotics. In addition, Mtb can slow or stop its cell replication and become drug tolerant. The Mtb kinase and phosphatase enzymes studied by the Grundner Lab are potential new targets for treating TB, including when Mtb is in a nonreplicating stage.

Drug targets in phosphosignaling networks

Dr. Grundner uses unbiased, systems-wide approaches to establish and investigate phosphosignaling networks that Mtb uses to respond to environmental conditions or to evade the immune system and antibiotics. The Grundner team also identified a new protein modification, protein tyrosine phosphorylation in Mtb, in addition to identifying a kinase that acts as the switch between latent and replicating states in the bacteria.

The Grundner Lab also showed extensive interactions between two phosphosignaling systems in Mtb. The researchers discovered that in Mtb, O-phosphorylation systems that control protein activity through serine/threonine kinases regulate separate, two-component phosphosignaling systems. These discoveries reveal new, uniquely bacterial themes in Mtb phosphosignaling that expand the options for Mtb-specific TB therapeutics.

Activity-based proteomics and whole-cell screening

TB is not the only disease that is exacerbated by populations of persistent, nonreplicating cells. The Grundner Lab applies their expertise in activity-based chemical proteomics to identify potential therapeutic targets in Mtb and in other infectious agents such as Plasmodium falciparum, a cause of malaria. This method differs from typical proteomics because it detects the function of proteins instead of only their abundance.

Activity-based proteomics selectively labels proteins using a function-based probe, which can be a molecular starting point for target-based drug discovery. Labeled proteins are then identified using mass spectrometry, and the technique reveals the function of the identified proteins (e.g., kinase, ATPase). Dr. Grunder uses activity-based proteomics to study individual target proteins and also to functionally annotate large protein collections.

The Grundner Lab also has expertise in whole-cell screening of drug candidates or compound libraries, including against replicating and nonreplicating Mtb. Using whole-cell screening with follow-up testing against drug-tolerant persistent cells, they identified an anilinoquinazoline compound with potential kinase-inhibitory activity as a strong candidate for new tuberculosis therapeutics.

Dr. Grundner is interested in partnerships that use his expertise in identifying targets and candidate drug compounds for infectious diseases, including by screening compound libraries.

Stage of Development

• Preclinical in vitro

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement
• Activity-based proteomics
• Whole-cell screening of Mycobacterium tuberculosis

Learn More

• Christoph Grundner, PhD
• Grundner Lab
• Grundner Lab tuberculosis outer membrane transporters
• Seattle Children’s Featured Research – Phosphokinases

Publications

1. Liu SH, Call DH, Kitata RB … Grundner C, et al. Evaluation of data-independent acquisition-based phosphoproteomics analysis in mammalian and bacterial systems. J Proteome Res. 2026;25(5):2374-2384.
2. Frando A, Boradia V, Grundner C. Regulatory intersection of two-component system and ser/thr protein kinase signaling in Mycobacterium tuberculosis. J Mol Biol. 2024;436(2):168379.
3. Frando A, Grundner C. More than two components: complexities in bacterial phosphosignaling. mSystems. 2024;9(5):e0028924.
4. Nandakumar M, Ollodart A, Fleck N … Grundner C. Dual inhibition of Mycobacterium tuberculosis and the host TGFBR1 by an anilinoquinazoline. J Med Chem. 2023;66(21):14724-14734.
5. Frando A, Boradia V, Gritsenko M … Grundner C. The Mycobacterium tuberculosis protein O-phosphorylation landscape. Nat Microbiol. 2023;8(3):548-561.

Last updated June 2026