Ribosome hibernation: a new molecular framework for targeting nonreplicating persisters of mycobacteria

Abstract

Treatment of tuberculosis requires a multi-drug regimen administered for at least 6 months. The long-term chemotherapy is attributed in part to a minor subpopulation of nonreplicating Mycobacterium tuberculosis cells that exhibit phenotypic tolerance to antibiotics. The origins of these cells in infected hosts remain unclear. Here we discuss some recent evidence supporting the hypothesis that hibernation of ribosomes in M. tuberculosis, induced by zinc starvation, could be one of the primary mechanisms driving the development of nonreplicating persisters in hosts. We further analyse inconsistencies in previously reported studies to clarify the molecular principles underlying mycobacterial ribosome hibernation.

New perspectives on an ancient pathogen: thoughts for World Tuberculosis Day 2022

“…Borlee et al [14] use compounds secreted by amoeba as a novel approach to disrupt mycobacterial biofilms. Hibernation of ribosomes induced by zinc starvation also results in antibiotic tolerance [15]. Therapies that target the host are another attractive approach to killing antibiotic tolerant populations, as discussed by Rankine-Wilson et al [16].…”

Perspectives on Metals in Microbiology

“…For example, certain zinc-dependent ribosomal proteins can be replaced by zinc-independent counterparts during conditions of zinc deficiency. The review by Li and colleagues [7], discusses how such ribosome remodelling in M. tuberculosis in response to zinc-starvation leads to ribosome hibernation, and could be a primary mechanism driving the development of nonreplicating persister bacteria that exhibit phenotypic tolerance to antibiotics.…”

“…For example, certain zinc-dependent ribosomal proteins can be replaced by zinc-independent counterparts during conditions of zinc deficiency. The review by Li and colleagues [7], discusses how such ribosome remodelling in M. tuberculosis in response to zinc-starvation leads to ribosome hibernation, and could be a primary mechanism driving the development of nonreplicating persister bacteria that exhibit phenotypic tolerance to antibiotics. The above-mentioned review by Serafini [3] also highlights how the remodelling of carbon metabolism in iron-starved growth-arrested M. tuberculosis, via increased production of alternative iron-independent enzymes, allows carbon metabolism to proceed during the iron-starved dormant state.…”

A bacterial ribosome hibernation factor with evolutionary connections to eukaryotic protein synthesis

“…These factors bind to ribosomes, shielding their vulnerable active centres from degradation by cellular nucleases [11][12][13] . Due to this critical protective role, the depletion of dormancy factors causes the accumulation of damaged ribosomes and drastically impairs the ability of cells to recover their growth after starvation, stress, or drug treatment [14][15][16][17] .…”