The importance of gaining a deeper understanding on antibiotic resistance and developing tools to circumvent and prevent it can hardly be overstated. This study attempts at exploring the possibility of controlling Double-Stranded Break Repair (DSBR) as a way of increasing antibiotic effectiveness and reducing the risk of de-novo emergence of antibiotic resistance.
For studying the effects of inhibited DSBR, a set of candidate genes are selected and mutations on the same have been used as a way of disrupting DSBR. Colonies with bacteria that have mutations on these genes show a marked decrease in the Minimum Inhibitory Concentration (MIC) over a host of antibiotic drugs. (Fig. 1)
However, for antibiotic drugs that affect the ribosome and folate biosynthesis (kanamycin and trimethoprim), the mutants show significant decrease in cell viability only when treated with very high concentrations (10x MIC) of antibiotics. One wonders how strong this effect is across antibiotics and how general can the effect of DSBR will be for various other antibiotics that are not studied in this work.
One way in which antimicrobial resistance might emerge in an accelerated manner in bacterial populations is by a marked increase in mutagenesis (SOS response). This study also shows a definite link between inhibition of DSBR and decreased probability of an SOS response. Combined, these results show that inhibiting DSBR may not just allow one to work with antibiotic resistant strains as and when they emerge, but also perhaps avoid the emergence of new resistant strains. This indeed looks very promising.
However, a major caveat, as previously mentioned, is how generally applicable could this be? The study does show a marked decrease in MIC for many antibiotics, which clearly shows that this is an important direction to be pursued. But it is needed that we are careful about when and how does the usefulness of DSBR inhibition stop, and that we are acutely aware of the limitations.
Another aspect where more exploration is required is a more detailed, mechanistic understanding on how the SOS response also gets induced along with DNA repair pathways. Both of these, in retrospect, seem to be processes that are physiologically at odds with each other. It would therefore be interesting to look at them, and the underlying mechanistic connection, from an evolutionary point of view.