Details

Autor(en) / Beteiligte

• Plé, Coline
• Tam, Heng-Keat
• Vieira Da Cruz, Anais
• Compagne, Nina
• Jiménez-Castellanos, Juan-Carlos
• Müller, Reinke T.
• Pradel, Elizabeth
• Foong, Wuen Ee
• Malloci, Giuliano
• Ballée, Alexia
• Kirchner, Moritz A.
• Moshfegh, Parisa
• Herledan, Adrien
• Herrmann, Andrea
• Deprez, Benoit
• Willand, Nicolas
• Vargiu, Attilio Vittorio
• Pos, Klaas M.
• Flipo, Marion
• Hartkoorn, Ruben C.

Titel

Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

Ist Teil von

• Nature communications, 2022-01, Vol.13 (1), p.115-115, Article 115

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Efflux 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. Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.