Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Inhibition of Efflux Pumps by Monoterpene (α-pinene) and Impact on Staphylococcus aureus Resistance to Tetracycline and Erythromycin

Author(s): Priscilla R. Freitas, Ana Carolina J. de Araújo, Cristina R. Barbosa, Débora F. Muniz, Saulo R. Tintino, Jaime Ribeiro-Filho, José P. Siqueira Júnior, José M.B. Filho, Gabriela R. de Sousa and Henrique D.M. Coutinho*

Volume 22, Issue 2, 2021

Published on: 30 July, 2020

Page: [123 - 126] Pages: 4

DOI: 10.2174/1389200221999200730212721

Price: $65

Abstract

Introduction: Infectious diseases have been responsible for an increasing number of deaths worldwide. Staphylococcus aureus has been recognized as one of the most notable causative agents of severe infections, while efflux pump (EP) expression is one of the main mechanisms associated with S. aureus resistance to antibiotics.

Objective: This study aimed to investigate the potential of α-pinene as an efflux pump inhibitor in species of S. aureus carrying the TetK and MrsA proteins.

Methods: The minimum inhibitory concentrations (MIC) of α-pinene and other efflux pump inhibitors were assessed using serial dilutions of each compound at an initial concentration above 1024 μg/mL. Solutions containing culture medium and bacterial inoculums were prepared in test tubes and subsequently transferred to 96-well microdilution plates. The modulation of ethidium bromide (EtBr) and antibiotics (tetracycline and erythromycin) was investigated through analysis of the modification in their MICs in the presence of a subinhibitory concentration of α-pinene (MIC/8). Wells containing only culture medium and bacterial inoculums were used as negative control. Carbonyl cyanide m-chlorophenylhydrazone (CCCP) was used as a positive control.

Results: The MIC of ethidium bromide against S. aureus strains RN-4220 and IS-58 was reduced by association with α-pinene. This monoterpene potentiated the effect of tetracycline against the IS-58 strain but failed in modulating the antibacterial effect of erythromycin against RN-4220, suggesting a selective inhibitory effect on the TetK EP by α- pinene.

Conclusion: In conclusion, α-pinene has promising effects against S.aureus strains, which should be useful in the combat of antibacterial resistance associated with EP expression. Nevertheless, further research is required to fully characterize its molecular mechanism of action as an EP inhibitor.

Keywords: α-pinene, monoterpene, Staphylococcus aureus, TetK protein, MrsA protein, efflux pump inhibitors.

« Previous Next »
Graphical Abstract

[1]
Mota, F.S.; Oliveira, H.A.; Souto, R.C.F. Perfil e prevalência de resistência aos antimicrobianos de bactérias Gram-negativas isoladas de pacientes de uma unidade de terapia intensiva. RBAC, 2018, 50, 270-277.
[http://dx.doi.org/10.21877/2448-3877.201800740]
[2]
Loubet, P.; Burdet, C.; Vindrios, W.; Grall, N.; Wolff, M.; Yazdanpanah, Y.; Andremont, A.; Duval, X.; Lescure, F-X. Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review. Clin. Microbiol. Infect., 2018, 24(2), 125-132.
[http://dx.doi.org/10.1016/j.cmi.2017.07.003] [PMID: 28698037]
[3]
Steinig, E.J.; Duchene, S.; Robinson, D.A.; Monecke, S.; Yokoyama, M.; Laabei, M.; Slickers, P.; Andersson, P.; Williamson, D.; Kearns, A.; Goering, R.V.; Dickson, E.; Ehricht, R.; Ip, M.; O’Sullivan, M.V.N.; Coombs, G.W.; Petersen, A.; Brennan, G.; Shore, A.C.; Coleman, D.C.; Pantosti, A.; de Lencastre, H.; Westh, H.; Kobayashi, N.; Heffernan, H.; Strommenger, B.; Layer, F.; Weber, S.; Aamot, H.V.; Skakni, L.; Peacock, S.J.; Sarovich, D.; Harris, S.; Parkhill, J.; Massey, R.C.; Holden, M.T.G.; Bentley, S.D.; Tong, S.Y.C. Evolution and global transmission of a multidrug-resistant, community-associated methicillin-resistant Staphylococcus aureus lineage from the Indian subcontinent. MBio, 2019, 10(6), 10.
[http://dx.doi.org/10.1128/mBio.01105-19] [PMID: 31772058]
[4]
McGuinness, W.A.; Malachowa, N.; DeLeo, F.R. Focus: infectious diseases: vancomycin resistance in Staphylococcus aureus. Yale J. Biol. Med., 2017, 90(2), 269-281.
[PMID: 28656013]
[5]
Hamilton, S.M.; Alexander, J.A.N.; Choo, E.J.; Basuino, L.; da Costa, T.M.; Severin, A.; Chung, M.; Aedo, S.; Strynadka, N.C.J.; Tomasz, A.; Chatterjee, S.S.; Chambers, H.F. High-level resistance of Staphylococcus aureus to β-lactam antibiotics mediated by penicillin-binding protein 4 (PBP4). Antimicrob. Agents Chemother., 2017, 61(6), 02727-16.
[http://dx.doi.org/10.1128/AAC.02727-16] [PMID: 28373193]
[6]
da Costa, A.L.P.; Junior, A.C.S.S. Resistência bacteriana aos antibióticos e Saúde Pública: uma breve revisão de literatura. Estação Científica, 2017, 7, 45-57.
[http://dx.doi.org/10.18468/estcien.2017v7n2.p45-57]
[7]
Antonio, N.S.; Oliveira, A.C.; Canesini, R.; Rocha, J.R.; Pereira, R.E.P. Mecanismos de resistência bacteriana. Rev. Cient. Elet. Med. Vet., 2009, 200, 4.
[8]
Tintino, S.R.; Morais-Tintino, C.D.M.; Campina, F.F.; Pereira, R.L. Costa, Mdo.S.; Braga, M.F.B.M.; Limaverde, P.W.; Andrade, J.C.; Siqueira-Junior, J.P.; Coutinho, H.D.M.; Balbino, V.Q.; Leal-Balbino, T.C.; Ribeiro-Filho, J.; Quintans-Júnior, L.J. Action of cholecalciferol and alpha-tocopherol on Staphylococcus aureus efflux pumps. EXCLI J., 2016, 15, 315-322.
[PMID: 27298617]
[9]
Dos Santos, J.F.S.; Tintino, S.R.; de Freitas, T.S.; Campina, F.F. de A Menezes, I.R.; Siqueira-Júnior, J.P.; Coutinho, H.D.M.; Cunha, F.A.B. In vitro e in silico evaluation of the inhibition of Staphylococcus aureus efflux pumps by caffeic and gallic acid. Comp. Immunol. Microbiol. Infect. Dis., 2018, 57, 22-28.
[http://dx.doi.org/10.1016/j.cimid.2018.03.001] [PMID: 30017074]
[10]
Song, Q.; Wu, J.; Xu, Z.; Ruan, P. Methicillin-sensitive Staphylococcus aureus and emerging dominant sequence type 188 Staphylococcus aureus in severe community-associated infections. Int. J. Antimicrob. Agents, 2018, 51(3), 533-534.
[http://dx.doi.org/10.1016/j.ijantimicag.2018.01.013] [PMID: 29371102]
[11]
Dhar, P.; Chan, P.; Cohen, D.T.; Khawam, F.; Gibbons, S.; Snyder-Leiby, T.; Dickstein, E.; Rai, P.K.; Watal, G. Synthesis, antimicrobial evaluation, and structure-activity relationship of α-pinene derivatives. J. Agric. Food Chem., 2014, 62(16), 3548-3552.
[http://dx.doi.org/10.1021/jf403586t] [PMID: 24716724]
[12]
Rufino, A.T.; Ribeiro, M.; Judas, F.; Salgueiro, L.; Lopes, M.C.; Cavaleiro, C.; Mendes, A.F. Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity. J. Nat. Prod., 2014, 77(2), 264-269.
[http://dx.doi.org/10.1021/np400828x] [PMID: 24455984]
[13]
Javadpour, M.M.; Juban, M.M.; Lo, W.S.; Bishop, S.M.; Alberty, J.B.; Mann, C.M.; Markhan, J.L. A new method for determine the minim um inhibitory concentration of essential oils. J. Appl. Microbiol., 1996, 84, 538-544.
[14]
Coutinho, H.D.M.; Costa, J.G.M.; Lima, E.O.; Falcão-Silva, V.S.; Siqueira-Júnior, J.P. Enhancement of the antibiotic activity against a multiresistant Escherichia coli by Mentha arvensis L. and chlorpromazine. Chemotherapy, 2008, 54(4), 328-330.
[http://dx.doi.org/10.1159/000151267] [PMID: 18698137]
[15]
Tintino, S.R.; Oliveira-Tintino, C.D.M.; Campina, F.F.; Limaverde, P.W.; Pereira, P.S.; Siqueira-Junior, J.P.; Coutinho, H.D.M.; Quintans-Júnior, L.J.; da Silva, T.G.; Leal-Balbino, T.C. Vitamin K enhances the effect of antibiotics inhibiting the efflux pumps of Staphylococcus aureus strains. Med. Chem. Res., 2018, 27, 261-267.
[http://dx.doi.org/10.1007/s00044-017-2063-y]
[16]
Kozioł, A.; Stryjewska, A.; Librowski, T.; Sałat, K.; Gaweł, M.; Moniczewski, A.; Lochyński, S. An overview of the pharmacological properties and potential applications of natural monoterpenes. Mini Rev. Med. Chem., 2014, 14(14), 1156-1168.
[http://dx.doi.org/10.2174/1389557514666141127145820] [PMID: 25429661]
[17]
Salehi, B.; Upadhyay, S.; Orhan, I.E.; Jugran, A.K.; Jayaweera, S.L.D.; Dias, D.A.; Sharopov, F.; Taheri, Y.; Martins, N.; Baghalpour, N. Therapeutic potential of α-and β-pinene: a miracle gift of nature. Biomolecules, 2019, 9, 738.
[http://dx.doi.org/10.3390/biom9110738]
[18]
Limaverde, P.W.; Campina, F.F.; da Cunha, F.A.B.; Crispim, F.D.; Figueredo, F.G.; Lima, L.F. Datiane de M Oliveira-Tintino, C.; de Matos, Y.M.L.S.; Morais-Braga, M.F.B.; Menezes, I.R.A.; Balbino, V.Q.; Coutinho, H.D.M.; Siqueira-Júnior, J.P.; Almeida, J.R.G.S.; Tintino, S.R. Inhibition of the TetK efflux-pump by the essential oil of Chenopodium ambrosioides L. and α-terpinene against Staphylococcus aureus IS-58. Food Chem. Toxicol., 2017, 109(Pt 2), 957-961.
[http://dx.doi.org/10.1016/j.fct.2017.02.031] [PMID: 28238773]
[19]
Pereira da Cruz, R.; Sampaio de Freitas, T.; Socorro Costa, M.D.; Lucas Dos Santos, A.T.; Ferreira Campina, F.; Pereira, R.L.S.; Bezerra, J.W.A.; Quintans-Júnior, L.J.; De Souza Araújo, A.A.; Júnior, J.P.S.; Iriti, M.; Varoni, E.M.; Menezes, I.R.A.; Melo Coutinho, H.D.; Morais-Braga, M.F.B. Effect of α-bisabolol and Its β-cyclodextrin complex as TetK and NorA efflux pump inhibitors in Staphylococcus aureus strains. Antibiotics (Basel), 2020, 9(1), 28.
[http://dx.doi.org/10.3390/antibiotics9010028] [PMID: 31947642]
[20]
Freitas, P.R.; de Araújo, A.C.J.; Barbosa, C.R.S.; Muniz, D.F.; da Silva, A.C.A.; Rocha, J.E.; Oliveira-Tintino, C.D.M.; Ribeiro-Filho, J.; da Silva, L.E.; Confortin, C. GC-MS-FID and potentiation of the antibiotic activity of the essential oil of Baccharis reticulata (ruiz & pav.) pers. and α-pinene. Ind. Crops Prod., 2020.145112106
[http://dx.doi.org/10.1016/j.indcrop.2020.112106]
[21]
Bhardwaj, A.K.; Mohanty, P. Bacterial efflux pumps involved in multidrug resistance and their inhibitors: rejuvinating the antimicrobial chemotherapy. Recent Pat. Antiinfect. Drug Discov, 2012, 7(1), 73-89.
[http://dx.doi.org/10.2174/157489112799829710] [PMID: 22353004]
[22]
Oliveira-Tintino, C.D.M.; Tintino, S.R.; Limaverde, P.W.; Figueredo, F.G.; Campina, F.F.; da Cunha, F.A.B.; da Costa, R.H.S.; Pereira, P.S.; Lima, L.F. de Matos, YMLS Inhibition of the essential oil from Chenopodium ambrosioides L. and α-terpinene on the NorA efflux-pump of Staphylococcus aureus. Food Chem., 2018, 262, 72-77.
[23]
Bakkali, F.; Averbeck, S.; Averbeck, D.; Idaomar, M. Biological effects of essential oils - a review. Food Chem. Toxicol., 2008, 46(2), 446-475.
[http://dx.doi.org/10.1016/j.fct.2007.09.106] [PMID: 17996351]

Rights & Permissions Print Cite
Article Metrics
38
2
© 2024 Bentham Science Publishers | Privacy Policy