The 1,8-naphthyridines sulfonamides are NorA efflux pump inhibitors.

de Morais Oliveira-Tintino, Cícera Datiane; Feitosa Muniz, Débora; Dos Santos Barbosa, Cristina Rodrigues; Silva Pereira, Raimundo Luiz; Maria Begnini, Iêda; Andrade Rebelo, Ricardo; da Silva, Luiz Everson; Lucio Mireski, Sandro; Caroline Nasato, Michele; Lacowicz Krautler, Maria Isabel; Silvino Pereira, Pedro; Galberto Martins da Costa, José; Galvão Rodrigues, Fabiola Fernandes; Rodrigues Teixeira, Alexandre Magno; Ribeiro-Filho, Jaime; Relison Tintino, Saulo; de Menezes, Irwin Rose Alencar; Melo Coutinho, Henrique Douglas; da Silva, Teresinha Gonçalves

BACKGROUND AND OBJECTIVE Efflux pumps are transmembrane proteins associated with bacterial resistance mechanisms. Bacteria use these proteins to actively transport antibiotics to the extracellular medium, preventing the pharmacological action of these drugs. This study aimed to evaluate in vitro the antibacterial activity of 1,8-naphthyridines sulfonamides as well as its ability to inhibit efflux systems of Staphylococcus aureus strains expressing different levels of the NorA efflux pump. METHODS The broth microdilution test was performed to assess antibacterial activity. Efflux pump inhibition was evaluated in silico by molecular docking and in vitro,by fluorometric tests, and determining the minimum inhibitory concentration (MIC). The MIC was determined in the association between 1,8-naphthyridine and norfloxacin or ethidium bromide. RESULTS The 1,8-naphthyridines did not show direct antibacterial activity. In contrast, they effectively reduced the MIC of multidrug-resistant bacteria by associating with norfloxacin and ethidium bromide, in addition to increasing the fluorescence emission of this. The in silico analysis addressing the binding between NorA and 1,8-naphthyridines suggests that hydrogen bonds and hydrophilic interactions represent the interactions with the most favorable binding energy, corroborating the experimental data. CONCLUSION In conclusion, our data suggest that 1,8-naphthyridines sulfonamides inhibit bacterial resistance through molecular mechanisms associated with inhibition of the NorA efflux pump in S. aureus strains.