Exploiting the fitness cost of antibiotic resistance mutations to selectively eliminate resistant bacteria

Exploiting the fitness cost of antibiotic resistance mutations to selectively eliminate resistant bacteria

  • Datum: 08.06.2021
  • Uhrzeit: 11:00
  • Vortragende(r): Roberto Balbontin (Institute Gulbenkian of Science, Portugal)
  • Ort: virtuelle Plattform
  • Gastgeber: Javier Lopez-Garrido
Exploiting the fitness cost of antibiotic resistance mutations to selectively eliminate resistant bacteria

Antibiotic resistance often generates defects in bacterial growth known as fitness cost. As the cost is one of the main biological factors determining the prevalence of resistances upon reducing antibiotics use, understanding its causes is extremely important. Both compensatory evolution of double-resistant bacteria and epistatic interactions between resistance mutations that affect transcription and translation in Escherichia coli indicated the existence of additional factors contributing to their fitness cost, alongside altered protein synthesis. We found that the fitness costs of these antibiotic resistance mutations strongly correlate with double-strand DNA breaks, which are generated via uncoupling between transcription and translation, 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 fitness cost of resistance can be increased by targeting the RNase HI, which specifically degrades R-loops. We show that lack of RNase HI function drives resistant clones to extinction in populations with high initial frequency of resistance, both in laboratory conditions and in a mouse model of gut colonization. This revealed RNase HI as a target specific against resistant bacteria, which we validated using a repurposed drug. In summary, we uncovered key mechanisms underlying the fitness cost of antibiotic resistance mutations that can be exploited to specifically eliminate resistant bacteria.

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