#FEMSmicroBlog: Bacteria adapting to small amounts of antibiotics

22-09-2022

Microbial resistance to antibiotics represents a major issue when treating infectious diseases. Most studies focus on the bacterial response to lethal antibiotic concentrations, yet bacteria often encounter lower antibiotic doses that still allow their growth. This can lead to the development and selection of resistance, although the molecular mechanisms behind this adaptation are not always well understood. The study “Non-essential tRNA and rRNA modifications impact the bacterial response to sub-MIC antibiotic stress” in microLife looks at new mechanisms of how bacteria adapt to sub-inhibitory concentrations of antibiotics. On the #FEMSmicroBlog, Louna Fruchard talks about a new link between non-coding RNAs and antibiotic tolerance. #FascinatingMicrobes

 

Why we need to consider sub-minimal inhibitory concentrations of antibiotics

Through antibiotic overuse and misuse in clinical and farming contexts, bacteria encounter gradients of antibiotics in human bodies, soil or water. As such, sub-inhibitory concentrations of antibiotics push bacteria to come up with sophisticated mechanisms to tolerate and resist antibiotic attacks.

Resistance designates the ability of a bacterial cell to withstand and grow during antibiotic treatment. On the other hand, tolerance — also associated with antibiotic treatment failure — refers to the extension of the period during which a bacterial population can survive the transient exposure to antibiotics.

Previous studies showed that low doses of antibiotics act as stressors to induce a transient phenotypic tolerance to high doses of antibiotics. Yet, characterizing the bacterial responses to such stress and its impact on resistance and tolerance needs to be comprehensively clarified.

Low doses of antibiotics act as stressors in bacteria and induce a transient phenotypic tolerance to high doses of antibiotics.

The study Non-essential tRNA and rRNA modifications impact the bacterial response to sub-MIC antibiotic stress” in microLife aims at uncovering new genes involved in survival and growth under non-lethal antibiotic concentrations. The work focuses on the pathogen Vibrio cholerae, the bacteria responsible for the deadly cholera disease.

A comprehensive genome-scaled gene interruption library was constructed composed of ~500’000 mutant strains that collectively contained insertions in all non-essential genes. A high-throughput method allowed to determine for each gene disruption whether the bacteria could still thrive in the presence of 50% of the minimum inhibitory concentration (MIC) of various antibiotics.

 

Modifying tRNA and rRNA genes to tolerate antibiotics

Results from this study point to a central role of genes that encode RNA modification proteins in response to low-dose antibiotic stress. Specifically, non-coding transfer RNA (tRNA) and ribosomal RNA (rRNA) are the main actors of messenger RNA (mRNA) translation into proteins: rRNAs as important constituents of ribosomes and tRNA delivering the relevant amino acid to the synthesized protein.

Bacteria modify their rRNA and tRNA when under antibiotic stress.
Bacteria modify tRNA and rRNA under antibiotic stress. From Babosan et al. (2022).

Proteins that modify tRNA and rRNA can have different enzymatic functions. For example, they can methylate specific bases or change a specific nucleoside to pseudouridine, dihydrouridine or queuosine. Such modifications of the tRNA or rRNA further influence the protein translation rate, fidelity, precision of codon decoding and, therefore, the composition of the bacterial proteome.

The study found that some of these genes involved in RNA modification appear to be beneficial for bacterial growth in sub-MICs. Yet, others prove detrimental. Furthermore, the fitness defect or advantage conferred by the RNA modification appears to be antibiotic-specific.

Modifying tRNA or rRNA in response to antibiotic stress changes the bacterial proteome and helps them cope with the antibiotic attack.

None of those identified t/rRNA modification genes was previously associated with any antibiotic resistance phenotype. These results thus suggest that bacteria can alter their RNA modification profiles according to antibiotic pressure. Additionally, it seems that the resulting variations in translation and codon recognition could be critical factors in the bacterial stress response.

Taken together, this study highlights the existence of an epigenetic or epitranscriptomic control of the bacterial response to antibiotic stress at the RNA level. These results could be the basis for future studies to develop antibiotics that inhibit the translation of specific proteins, for example, virulence factors or antibiotic resistance genes.

 

About the author of this story

Louna Fruchard studied microbiology and genetics at Sorbonne University. She is currently carrying out a PhD in the Bacterial Genome Plasticity laboratory at the Pasteur Institute in Paris. Louna is studying the role of tRNA modifications in bacterial adaptation to environmental stress and more particularly to sublethal antibiotic stress and mainly works on Vibrio cholerae.

About this blog section

The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.

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