# Origins of zinc starvation in Mycobacterium tuberculosis during chronic infection

> **NIH NIH R21** · WADSWORTH CENTER · 2021 · $223,662

## Abstract

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.

## Key facts

- **NIH application ID:** 10286274
- **Project number:** 1R21AI163599-01
- **Recipient organization:** WADSWORTH CENTER
- **Principal Investigator:** Anil Kumar Ojha
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $223,662
- **Award type:** 1
- **Project period:** 2021-06-08 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10286274

## Citation

> US National Institutes of Health, RePORTER application 10286274, Origins of zinc starvation in Mycobacterium tuberculosis during chronic infection (1R21AI163599-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10286274. Licensed CC0.

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