ArticleMolecular biology and evolution2021
DNA Breaks-Mediated Fitness Cost Reveals RNase HI as a New Target for Selectively Eliminating Antibiotic-Resistant Bacteria.
Article in Molecular biology and evolution, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- Identification of gene targets that potentiate the action of rifampicin onMicrobiology (Reading, England) · 2024Article
- New option: targeting RNase J and RNase HI in the fight against multi-drug-resistant tuberculosis.Annals of medicine and surgery (2012) · 2024Article
- CRISPR-Cas Systems in the Fight Against Antimicrobial Resistance: Current Status, Potentials, and Future Directions.Infection and drug resistance · 2024Review
- Epistasis decreases with increasing antibiotic pressure but not temperature.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Analysis of a Cell Wall Mutant Highlights Rho-Dependent Genome Amplification Events in Staphylococcus aureus.Microbiology spectrum · 2022Article
- RNase HI Depletion Strongly Potentiates Cell Killing by Rifampicin in Mycobacteria.Antimicrobial agents and chemotherapy · 2022Article
- Strong selective environments determine evolutionary outcome in time-dependent fitness seascapes.Evolution letters · 2022Article
- Rapid Decline of Ceftazidime Resistance in Antibiotic-Free and Sublethal Environments Is Contingent on Genetic Background.Molecular biology and evolution · 2022Article
- Article
- Evolutionary Pathways and Trajectories in Antibiotic Resistance.Clinical microbiology reviews · 2021Article
- Genomic and Transcriptomic Analysis of BovineFrontiers in veterinary science · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Antibiotic resistance often generates defects in bacterial growth called fitness cost. Understanding the causes of this cost is of paramount importance, as it is one of the main determinants of the prevalence of resistances upon reducing antibiotics use. Here we show that the fitness costs of antibiotic resistance mutations that affect transcription and translation in Escherichia coli strongly correlate with DNA breaks, which are generated via transcription-translation uncoupling, increased formation of RNA-DNA hybrids (R-loops), and elevated replication-transcription conflicts. We also demonstrated that the mechanisms generating DNA breaks are repeatedly targeted by compensatory evolution, and that DNA breaks and the cost of resistance can be increased by targeting the RNase HI, which specifically degrades R-loops. We further show that the DNA damage and thus the fitness cost caused by lack of RNase HI function drive resistant clones to extinction in populations with high initial frequency of resistance, both in laboratory conditions and in a mouse model of gut colonization. Thus, RNase HI provides a target specific against resistant bacteria, which we validate using a repurposed drug. In summary, we revealed key mechanisms underlying the fitness cost of antibiotic resistance mutations that can be exploited to specifically eliminate resistant bacteria.
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Registered trials
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