# Alternative ribosomes and antibiotic tolerance in mycobacteria.

> **NIH NIH R01** · WADSWORTH CENTER · 2021 · $405,545

## Abstract

Project Summary
Evolutionarily distant bacterial species respond to zinc starvation by reprogramming their
ribosome assembly, in which the constitutive ribosomal proteins with zinc-binding motifs CXXC
(C+) are substituted with alternative zinc-free counterparts (C-) through a transcriptional de-
repression mechanism involving the zinc uptake regulator, ZurB. The alternative ribosomes
assembled with C- ribosomal proteins reduce the zinc requirement for cellular growth under
zinc-limiting conditions. Mycobacterium tuberculosis (Mtb), the etiological agent for tuberculosis
(TB), has four C+/C- ribosomal protein pairs. All four genes encoding C- proteins of the pair are
organized in an operon and are co-expressed through a ZurB-repressible promoter. Co-
expression implies simultaneous substitution of all four C+ proteins by C- paralogs, raising
questions about the influence of the substitutions on ribosomal response to antibiotics. We have
found that the alternative C- ribosomes in both Mtb and Mycobacterium smegmatis not only
reduce the zinc requirement for cellular growth, but also confer tolerance to clinically relevant
anti-TB ribosomal antibiotics. We further observed that Mtb express more alternative ribosomes
during chronic infection than in early acute phase. We thus hypothesize that expression of
alternative ribosomes are the primary reasons underlying the inefficacies of the clinically
established ribosomal antibiotics against TB. To facilitate improved targeting of mycobacterial
ribosomes we propose to: a) elucidate the mechanistic basis of differential responses of
constitutive (C+) and alternative (C-) ribosomes to antibiotics (aim 1), b) identify strategies to
target alternative (C-) ribosomes (aim 2) and c) determine the role of alternative ribosomes in
pathogenesis of Mtb (aim 3). These studies will ultimately lead to new strategies to target both
constitutive and alternative ribosomes in mycobacteria, and thus allow effective clearance of
mycobacterial infections.

## Key facts

- **NIH application ID:** 10165472
- **Project number:** 5R01AI132422-05
- **Recipient organization:** WADSWORTH CENTER
- **Principal Investigator:** Anil Kumar Ojha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,545
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-09-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165472

## Citation

> US National Institutes of Health, RePORTER application 10165472, Alternative ribosomes and antibiotic tolerance in mycobacteria. (5R01AI132422-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165472. Licensed CC0.

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