Summary Tuberculosis (TB) is a major public health burden in the world: over a million people die of the disease every year and an estimated one third of the world’s population harbor the pathogen Mycobacterium tuberculosis (Mtb). Treatment of TB requires 6 to 9 months of an antibiotic regimen comprising of multiple antibiotics. Difficulties in treatment of TB are largely attributed to non-inheritable drug resistance in the pathogen that are considered to be developed due to unique microenvironments in the host (e.g. nutrient depletion, hypoxia and antibiotic exposure). Recently, we uncovered one such condition: zinc starvation. In response to zinc starvation both Mycobacterium smegmatis and Mycobacterium tuberculosis induce ribosome remodeling and ribosome hibernation. Ribosome remodeling involves replacement of multiple ribosomal (r-) proteins containing the zinc-binding CXXC motif (therefore called C+ r-proteins) by their motif- free C- paralogues. Ribosome hibernation involves binding of mycobacterial protein Y (Mpy) to the decoding center of the C- ribosome. Ribosome remodeling occurs at a zinc concentration that permits growth, whereas ribosome hibernation occurs at a growth-restrictive concentration of zinc. Moreover, mycobacterial cells harboring remodeled and hibernating ribosomes are resistant to aminoglycosides and spectinamides. Furthermore, we demonstrated that zinc in the host lung environment during chronic Mtb infection is low enough to induce ribosome remodeling and Mpy- dependent resistance to streptomycin, an aminoglycoside used in the treatment of multi-drug resistant TB. However, the underlying cause for zinc starvation in Mtb during chronic infection is not known. Based on the idea that metal ion starvation during bacterial infections is an innate host defense strategy, called nutritional immunity, we propose to identify the components of host immune system responsible for zinc starvation in Mtb (Aim 1), and determine the potential of zinc oxide nanoparticles as an adjunct therapeutic (Aim 2). Upon completion of the project we will gain further insight into the cause of zinc starvation and related ribosome remodeling/hibernation in Mtb during chronic infection, and develop a therapeutic strategy to minimize the drug resistance caused by these changes to the ribosome in Mtb.