La risposta SOS nei batteri ed il repressore trascrizionale LexA: inibizione dell’adesione e della formazione del biofilm come strategia per la resistenza alle infezioni batteriche

The ever-increasing urgency of addressing the growing phenomenon of antimicrobial resistance is driving the scientific community to explore new strategies to combat what could soon represent the greatest threat to human health. The synthesis of new pharmacologically active molecules is not the most viable path due to the need for rapid intervention and the tendency of microorganisms to quickly develop resistance. Searching for alternative microbial targets distinct from those targeted by traditional antibiotics represents one of the most promising strategies, particularly in terms of not relying solely on antibiotic therapy. From this perspective, the SOS pathway is an excellent target since modulating this response essentially means modulating microbial pathogenicity mechanisms. Blocking the activation of the SOS response does not lead to microbial death; instead, it could enhance antibiotic therapy by preventing the activation of mechanisms to counteract the antibiotic's activity. The RecA/LexA pathway modulates the SOS response, where both proteins represent excellent targets for blocking the SOS response. RecA is the sensor for DNA damage, which activates LexA, the transcriptional repressor responsible for repressing about 60 genes in the SOS regulon. Of the two, LexA is the least explored target but is, in fact, the most promising. LexA is a protein that undergoes self-cleavage, a reaction induced by RecA. This reaction is facilitated by the catalytic dyad Ser119/Lys156. If LexA were treated as a serine enzyme, it would be possible to use serine protease inhibitors to block LexA and disrupt the cascade of events it initiates. Among the most promising serine protease inhibitors are boronic acid-based compounds, particularly notable for their low toxicity, making them safe for pharmaceutical application. As part of this research, we explored potential inhibitors of the LexA transcriptional repressor within a pool of boron-containing molecules by a drug-repurposing approach. This investigation confirmed the promising and versatile properties of boron-based compounds and demonstrated that these molecules can effectively interact with LexA, interfering with processes associated with its self-cleavage. In particular, we identified promising inhibitors belonging to the benzoxaborole category, which are already commercially available for treating various conditions.