Authors: Coline Plé, Heng-Keat Tam, Anais Vieira Da Cruz, Nina Compagne, Juan-Carlos Jiménez-Castellanos, Reinke T. Müller, Elizabeth Pradel, Wuen Ee Foong, Giuliano Malloci, Alexia Ballée, Moritz A. Kirchner, Parisa Moshfegh, Adrien Herledan, Andrea Herrmann, Benoit Deprez, Nicolas Willand, Attilio Vittorio Vargiu, Klaas M. Pos, Marion Flipo, Ruben C. Hartkoorn
Published: 2022-01-10
DOI: 10.1038/s41467-021-27726-2
Source: Full article
AbstractEfflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.