New Therapeutic Approaches for Tuberculosis
Targeting phosphosignaling pathways and non-replicating bacteria
The major focus of Dr. Christoph Grundner's research is phosphosignaling in Mycobacterium tuberculosis (Mtb). Phosphosignaling pathways transduce external signals into cellular responses via reversible protein phosphorylation. Kinase and phosphatase enzymes in these networks are potential therapeutic targets.
The Grundner lab uses unbiased, systems-wide approaches to determine the network connectivity and discover new, uniquely bacterial themes in Mtb phosphosignaling. The group identified extensive protein tyrosine phosphorylation in Mtb and a kinase that acts as the switch between latent and replicating states in the bacteria. The lab is exploring the phosphosignaling enzymes as drug targets by leveraging existing resources for targeting human kinases.
Many diseases are exacerbated by populations of persistent cells that are difficult to eradicate because they are not replicating and their metabolism in this state is unknown. The Grundner group finds vulnerable enzymes that might be drug targets in these non-replicating cells. They use activity-based proteomics to identify potential targets for Mtb and 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. Labeled proteins are identified using mass spectrometry. The technique reveals the function of the identified proteins such as protease or ATPase. The probe molecule can be a starting point for target-based drug discovery.
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
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Activity-based proteomics
- Mycobacterium tuberculosis whole-cell screening
- Ortega C, Frando A, Webb-Robertson BJ, Anderson LN, Fleck N, Flannery EL, ... Grundner C. A global survey of ATPase activity in Plasmodium falciparum asexual blood stages and gametocytes. Mol Cell Proteomics. 2018;17(1):111-120.
- Ortega C, Anderson LN, Frando A, Sadler NC, Brown RW, Smith RD, Wright AT, Grundner C.Systematic survey of serine hydrolase activity in Mycobacterium tuberculosis defines changes associated with persistence. Cell Chem Biol. 2016;23(2):290-298.
- Ortega C, Liao R, Anderson LN, Rustad T, Ollodart AR, Wright AT, Sherman DR, Grundner C. Mycobacterium tuberculosis Ser/Thr protein kinase B mediates an oxygen-dependent replication switch. PLoS Biol. 2014;12(1):e1001746.
- Kusebauch U, Ortega C, Ollodart A, Rogers RS, Sherman DR, Moritz RL, Grundner C. Mycobacterium tuberculosis supports protein tyrosine phosphorylation. Proc Natl Acad Sci USA. 2014;111(25):9265-70.
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