In vitro and in silico analysis of the efficiency of tetrahydropyridines as drug efflux inhibitors in Escherichia coli.
The objectives of this study were to evaluate tetrahydropyridine derivatives as efflux inhibitors and to understand the mechanism of action of the compounds by in silico studies. Minimum inhibitory concentration (MIC) determination, fluorometric methods and docking simulations were performed. The compounds NUNL02, NUNL09 and NUNL10 inhibited efflux, and NUNL02 is very likely a substrate of the transporter protein AcrB. Docking studies suggested that the mechanism of action could be by competition with substrate for binding sites and protein residues. We showed for the first time the potential of tetrahydropyridines as efflux inhibitors and highlighted compound NUNL02 as an AcrB-specific inhibitor. Docking studies suggested that competition is the putative mechanism of action of these compounds.
Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande-FURG, Rio Grande, Brazil.
Lande
L
Silva
Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande-FURG, Rio Grande, Brazil.
Lillian Lucas
LL
Carrion
Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande-FURG, Rio Grande, Brazil.
Andrea
A
von Groll
Grupo de Micobactérias, Unidade de Microbiologia Médica and Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Lisbon, Portugal.
Sofia Santos
SS
Costa
Grupo de Micobactérias, Unidade de Microbiologia Médica and Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Lisbon, Portugal.
Elisabete
E
Junqueira
Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande-FURG, Rio Grande, Brazil.
Daniela Fernandes
DF
Ramos
Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande-FURG, Rio Grande, Brazil.
Jéssica
J
Cantos
Centro de Ciências Computacionais, Universidade Federal do Rio Grande, Rio Grande, Brazil.
Vinicius Rosa
VR
Seus
Grupo de Micobactérias, Unidade de Microbiologia Médica and Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Lisbon, Portugal.
Isabel
I
Couto
Núcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, Brazil.
Liana da Silva
LD
Fernandes
Núcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, Brazil.
Hélio Gauze
HG
Bonacorso
Núcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, Brazil.
Marcos Antônio Pinto
MA
Martins
Núcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, Brazil.
Nilo
N
Zanatta
Grupo de Micobactérias, Unidade de Microbiologia Médica and Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Lisbon, Portugal.
Miguel
M
Viveiros
Centro de Ciências Computacionais, Universidade Federal do Rio Grande, Rio Grande, Brazil.
Karina S
KS
Machado
Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande-FURG, Rio Grande, Brazil. Electronic address: pedrefurg@gmail.com.
Pedro Eduardo
PE
Almeida da Silva
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects*; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; C083496:AcrB protein, E coli
AcrB; Competition; Efflux; Inhibitors