Christoph Grundner, Ph.D.

Tuberculosis (TB) control is threatened by the continued emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains such as multidrug-resistant TB and extensively drug-resistant TB. There are two especially promising strategies to limit the emergence of drug resistance. One is the targeting of dormant Mtb that becomes tolerant to TB drugs, meaning they become resistant to killing. The second is host-directed therapy, which involves manipulating the body's response to TB bacteria rather than targeting the bacteria themselves. We have identified a compound that kills Mtb through both approaches. We will test the effectiveness of this dually active compound in the mouse model of tuberculosis. Our hope is that this compound will impede the emergence of drug resistance.

Update:

We made significant progress on both Aims of this project: 1) To identify the targets of our dual specificity inhibitor and with that, a new mechanism of killing Mtb, and 2) to test the efficacy of the inhibitor in the mouse model of Mtb infection. Using resistance mutants generated in the lab combined with genome sequencing, we identified genes involved in the mechanism of action of the inhibitors. We identified additional chemical analogs with improved activity against Mtb and/or the host, and begun testing of the compounds in an intracellular macrophage killing assay and in the mouse.