RecA Inhibitor Mitigates Bacterial Antibiotic Resistance

Bacterial antibiotic resistance (AR) has become a critical global health threat. AR is mainly driven by adaptive resistance mutations and the horizontal gene transfer of resistance genes, both of which are enhanced by genome recombination. We previously discovered that genome recombination-mediated tRNA upregulation is important for AR, especially in the early stages. RecA is a crucial bacterial factor mediating genome recombination and the DNA damage response. Therefore, RecA inhibitors should be effective in reducing AR. In this study, we found that BRITE-338733 (BR), a RecA inhibitor, can prevent ciprofloxacin (CIP) resistance in subculturing Escherichia coli strain BW25113 in the early stages (up to the 7th generation). In the presence of BR, the tRNA was decreased, so the bacteria cannot evolve resistance via the tRNA upregulation-mediated AR mechanism. The RecA expression level was also not increased when treated with BR. Transcriptome sequencing revealed that BR could inhibit oxidative phosphorylation, the electron transport chain process, and translation, thereby reducing the bacterial energy state and protein synthesis. Also, the effective concentrations of BR do not harm human cell viability, indicating its clinical safety. These findings demonstrate that BR effectively delays the emergence of spontaneous AR by targeting RecA-mediated pathways. Our findings shed light on a new strategy to counteract clinical AR: applying BR with the antibiotics together at the beginning.