Valencene, Nootkatone and Their Liposomal Nanoformulations as Potential Inhibitors of NorA, Tet(K), MsrA, and MepA Efflux Pumps in <i>Staphylococcus aureus</i> Strains
Cícera Datiane de Morais Oliveira-Tintino,
Jorge Ederson Gonçalves Santana,
Gabriel Gonçalves Alencar,
Gustavo Miguel Siqueira,
Sheila Alves Gonçalves,
Saulo Relison Tintino,
Irwin Rose Alencar de Menezes,
João Pedro Viana Rodrigues,
Vanessa Barbosa Pinheiro Gonçalves,
Roberto Nicolete,
Jaime Ribeiro-Filho,
Teresinha Gonçalves da Silva,
Henrique Douglas Melo Coutinho
Affiliations
Cícera Datiane de Morais Oliveira-Tintino
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
Jorge Ederson Gonçalves Santana
Department of Antibiotics, Federal University of Pernambuco (UFPE), Recife 50670-901, PE, Brazil
Gabriel Gonçalves Alencar
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
Gustavo Miguel Siqueira
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
Sheila Alves Gonçalves
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
Saulo Relison Tintino
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
Irwin Rose Alencar de Menezes
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
João Pedro Viana Rodrigues
Oswaldo Cruz Foundation (Fiocruz Ceará), Eusébio 61773-270, CE, Brazil
Vanessa Barbosa Pinheiro Gonçalves
Oswaldo Cruz Foundation (Fiocruz Ceará), Eusébio 61773-270, CE, Brazil
Roberto Nicolete
Oswaldo Cruz Foundation (Fiocruz Ceará), Eusébio 61773-270, CE, Brazil
Jaime Ribeiro-Filho
Oswaldo Cruz Foundation (Fiocruz Ceará), Eusébio 61773-270, CE, Brazil
Teresinha Gonçalves da Silva
Department of Antibiotics, Federal University of Pernambuco (UFPE), Recife 50670-901, PE, Brazil
Henrique Douglas Melo Coutinho
Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-010, CE, Brazil
Valencene and nootkatone are aromatic sesquiterpenes with known biological activities, such as antimicrobial, antioxidant, anti-inflammatory, and antitumor. Given the evidence that encapsulation into nanosystems, such as liposomes, could improve the properties of several compounds, the present study aimed to evaluate the activity of these sesquiterpenes in their isolated state or in liposomal formulations against strains of Staphylococcus aureus carrying efflux pumps. The broth microdilution method evaluated the antibiotic-enhancing activity associated with antibiotics and ethidium bromide (EtBr). The minimum inhibitory concentration was assessed in strains of S. aureus 1199B, IS-58, and RN4220, which carry the efflux proteins NorA, Tet(K), and MsrA. In tests with strain 1199B, valencene reduced the MIC of norfloxacin and EtBr by 50%, while the liposomal formulation of this compound did not show a significant effect. Regarding the strain IS-58, valencene, and its nanoformulation reduced norfloxacin MIC by 60.3% and 50%, respectively. In the non-liposomal form, the sesquiterpene reduced the MIC of EtBr by 90%. Against the RN4220 strain, valencene reduced the MIC of the antibiotic and EtBr by 99% and 93.7%, respectively. Nootkatone and its nanoformulation showed significant activity against the 1199B strain, reducing the EtBr MIC by 21.9%. Against the IS-58 strain, isolated nootkatone reduced the EtBr MIC by 20%. The results indicate that valencene and nootkatone potentiate the action of antibiotics and efflux inhibitors in strains carrying NorA, Tet(K), and MsrA proteins, which suggests that these sesquiterpenes act as efflux pump inhibitors in S. aureus. Therefore, further studies are needed to assess the impact of incorporation into liposomes on the activity of these compounds in vivo.
