Inhibition of the LexA-reca protein interaction reduces the bacterial SOS responce to DNA damage

The worldwide emergence of antibiotic resistant bacteria poses a severe threat to human health by diminishing the effectiveness of the current drugs. In many bacteria exposure to environmental stress (including antibiotics) results in induction of the SOS response, potentially culminating in an increased mutation rate by de-repressing the error-prone DNA polymerases. In Escherichia coli, the response is controlled by the LexA repressor. The binding of the RecA recombinase to DNA facilitates the inactivation of LexA via autocatalytic proteolysis (cleavage). Preventing the LexA cleavage event inhibits the induction of the SOS response and reduces the evolution of antibiotic resistance in bacteria.;The current study aims to identify the specific interaction interface between LexA and the RecA nucleoprotein filament. This information can potentially be utilized to rationally design peptide-based drugs to inhibit LexA cleavage, hence reducing evolution of antibiotic resistance. Using in vitro LexA cleavage experiments, we identified the 40 amino acid long LexA truncation peptide that competitively inhibits interaction between the RecA nucleoprotein filament and LexA repressor. In addition, data from luciferase SOS reporter assays suggest that the LexA truncation peptide also inhibits induction of the SOS response in E. coli cells. Moreover, certain point mutations in this region of LexA affect the LexA-RecA interaction. Furthermore, using molecular docking approaches, we have predicted the RecA face of the LexA-RecA interaction interface. The current findings provide the foundation for the development of antibiotic drug additives that significantly reduce the evolution of antibiotic resistance by inhibiting induction of the bacterial SOS response.