par Maso, Lorenzo;Vascon, Filippo;Chinellato, Monica;Goormaghtigh, Frederic 
;Bellio, Pierangelo;Campagnaro, Enrica;Van Melderen, Laurence ;Ruzzene, Maria;Pardon, Els;Angelini, Alessandro;Celenza, Giuseppe;Steyaert, Jan;Tondi, Donatella;Cendron, Laura
Référence Structure, 30, 11, page (1479-1493.e9)
Publication Publié, 2022-11-01
;Bellio, Pierangelo;Campagnaro, Enrica;Van Melderen, Laurence ;Ruzzene, Maria;Pardon, Els;Angelini, Alessandro;Celenza, Giuseppe;Steyaert, Jan;Tondi, Donatella;Cendron, LauraRéférence Structure, 30, 11, page (1479-1493.e9)
Publication Publié, 2022-11-01
Article révisé par les pairs
| Résumé : | Antimicrobial resistance threatens the eradication of infectious diseases and impairs the efficacy of available therapeutics. The bacterial SOS pathway is a conserved response triggered by genotoxic stresses and represents one of the principal mechanisms that lead to resistance. The RecA recombinase acts as a DNA-damage sensor inducing the autoproteolysis of the transcriptional repressor LexA, thereby derepressing SOS genes that mediate DNA repair, survival to chemotherapy, and hypermutation. The inhibition of such pathway represents a promising strategy for delaying the evolution of antimicrobial resistance. We report the identification, via llama immunization and phage display, of nanobodies that bind LexA with sub-micromolar affinity and block autoproteolysis, repressing SOS response in Escherichia coli. Biophysical characterization of nanobody-LexA complexes revealed that they act by trapping LexA in an inactive conformation and interfering with RecA engagement. Our studies pave the way to the development of new-generation antibiotic adjuvants for the treatment of bacterial infections. |
