DNA breaks-mediated cost reveals RNase HI as a new target for selectively eliminating antibiotic resistance

Roberto Balbontín; Nelson Frazão; Isabel Gordo

We observed that replication-transcription conflicts contribute to the cost of resistance ( Figure 3 ), and that overproduction of DksA, involved in transcription-coupled DNA repair (53, 54) , reduces the cost of resistance ( Figure S2A ). Interestingly, DksA is also involved in preventing replicationtranscription conflicts (73) . Thus, prevention of the conflicts by DksA might also account for its beneficial effect on resistant bacteria, besides the enhancement of DNA repair. The involvement of replication-transcription conflicts in the cost of resistance is coherent with previous observations, such as the small cost of specific Rif R and/or Str R alleles in minimal medium (24, 74, 75) or the outcompetition of sensitive bacteria by resistant mutants in aging colonies (76, 77) . Interestingly, stable DNA replication (initiation of DNA replication at sites different from OriC) can be induced by lack of RNase HI or by conditions that activate SOS (78) . Thus, Rif R and Str R mutations, which induce SOS This detrimental runaway loop, as well as the effects of the environment on the cost described above ( Figure 1A and Figure 3C ), could potentially be exploited therapeutically, via concurrent chemical and dietary treatments designed to synergistically maximize the cost of resistance.