Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Coline Plé
(1)
,
Heng-Keat Tam
(2)
,
Anais Vieira da Cruz
(3)
,
Nina Compagne
(3)
,
Juan-Carlos Jiménez-Castellanos
(1)
,
Reinke Müller
(2)
,
Elizabeth Pradel
(1)
,
Wuen Ee Foong
(2)
,
Giuliano Malloci
(4)
,
Alexia Ballée
(3)
,
Moritz Kirchner
(2)
,
Parisa Moshfegh
(3)
,
Adrien Herledan
(3)
,
Andrea Herrmann
(2)
,
Benoit Deprez
(3)
,
Nicolas Willand
(3)
,
Attilio Vittorio Vargiu
(4)
,
Klaas Pos
(2)
,
Marion Flipo
(3)
,
Ruben Hartkoorn
(1)
Heng-Keat Tam
- Function : Author
- PersonId : 820114
- ORCID : 0000-0002-7894-1957
Elizabeth Pradel
- Function : Author
- PersonId : 758384
- ORCID : 0000-0003-3563-9325
- IdRef : 188213066
Wuen Ee Foong
- Function : Author
- PersonId : 820115
- ORCID : 0000-0003-2402-7729
Giuliano Malloci
- Function : Author
- PersonId : 784782
- ORCID : 0000-0002-5985-257X
Adrien Herledan
- Function : Author
- PersonId : 794927
- ORCID : 0000-0001-7258-498X
Benoit Deprez
- Function : Author
- PersonId : 757271
- ORCID : 0000-0002-2777-4538
- IdRef : 113949588
Attilio Vittorio Vargiu
- Function : Author
- PersonId : 776492
- ORCID : 0000-0003-4013-8867
Klaas Pos
- Function : Author
- PersonId : 803685
- ORCID : 0000-0001-9035-3827
- IdRef : 184016177
Marion Flipo
- Function : Author
- PersonId : 1080859
Ruben Hartkoorn
- Function : Author
- PersonId : 795131
- ORCID : 0000-0001-7315-1553
- IdRef : 242791131
Abstract
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.