Discovery of epigenetic modulators designed to treat and cure different tuberculosis endotypes by improving antimicrobial cellular immunity

Immune enhancing therapies represent an underexplored opportunity to meet the challenges of treatment failure in tuberculosis (TB).

My group has generated a platform for epigenetic modulation in chronic TB using histone deacetylase (HDAC) inhibitors that can alter immune cell differentiation and function.

We have shown that phenylbutyrate (PBA) can restore Mycobacterium tuberculosis (Mtb)-induced impairment of antimicrobial responses in macrophages and enhance clinical recovery of pulmonary TB.

Now, we advance our concept and recently discovered several HDAC inhibitors that can inhibit intracellular Mtb more effectively than PBA.

Next, we plan to exploit computer-aided methods including structure- and artificial intelligence-based design of potent HDAC modulators that can control the level of gene inhibition or activation in immune cells more precisely.

This work will focus on HDAC inhibition to restore antimicrobial genes, while HDAC activation repress excess activity of immunosuppressive genes.

Our panel of de novo HDAC modulators will be explored using a bioassay for high-content imaging and methods for cell-specific transcriptional regulation.

The effects of selected compounds on the function of innate and adaptive immune cells and stromal cells will be evaluated in relevant in vitro and in vivo infection models.

This project will promote personalized medicine in TB based on endotype-specific therapies for different groups of TB patients including multidrug-resistant TB.