Antibiotic efficacy in the tuberculosis cellular environments (360G-Wellcome-317609_Z_24_Z)

Chemotherapy of tuberculosis (TB) is not very efficient. We do not understand why it takes at least six months and a combination of four antibiotics to cure the disease. In the host, a subpopulation of Mycobacterium tuberculosis (Mtb), the bacteria that causes human TB can proliferate within host cells. However, our understanding of the cellular states that promote or restrict Mtb survival, and how they affect TB chemotherapy is lacking. We hypothesise that the intrinsic heterogeneity of infected cell populations contributes to antibiotic efficacy. Here, we aim to identify the host cellular states that increase or decrease antibiotic efficacy in TB across scales: in cellulo, using iPSC-derived human macrophages; in chip, using bioengineered iPSC- derived multicellular lung alveoli; and in vivo, using the susceptible mouse model of TB. By combining cutting-edge correlative antibiotic imaging approaches with genetically engineered fluorescent macrophages and Mtb to monitor macrophage function and Mtb location, we will define the subcellular, cellular and tissue microenvironments that impact antibiotic efficacy. These studies will (i) contribute to our understanding of how clinically relevant antibiotics work against intracellular bacteria, (ii) inform the design of combined therapies in TB, and (iii) develop relevant pipelines for the discovery of new antibiotics.