Reversal of multidrug resistance by amphiphilic morning glory resin glycosides in bacterial pathogens and human cancer cells

  • Jesús Lira-Ricárdez
  • Rogelio Pereda-MirandaEmail author


Pathogens that express resistance to multiple drugs are becoming the norm, complicating treatment and increasing human morbidity. Acylsugars or resin glycosides from the morning glory family (Convolvulaceae) are amphipathic modulators of the efflux pumps responsible for the drug-resistant phenotype in prokaryotic and eukaryotic cells. These inhibitory effects could be used to overcome the acquired resistance to common anticancer or antimicrobial drugs by lowering the current effective therapeutic doses, thus decreasing toxic side-effects in refractory malignancies. Active chemosensitizers identified by in vitro screening methods have demonstrated the therapeutic potential of resin glycosides for further exploration as coadjuvants to avoid drug resistance and restore the clinical utility of chemotherapy in treating infections and cancer. To date, more than 20 resin glycosides have been documented as inhibitors or modulators of efflux pumps, mainly isolated from species of the genus Ipomoea. Resin glycosides have shown the ideal structural features associated with multidrug-resistant efflux pump substrates. An overview is given to the acylsugar diversity and their amphiphilicity properties for bioactivity as leads of efflux pump inhibitors for drug development.


Acylsugar diversity Amphiphilicity Chemosensitizer Efflux pump inhibitor Multidrug-resistance 



Efflux pump


Efflux pump inhibitor


Ethidium bromide


Half maximal inhibitory concentration




Minimal inhibitory concentration








Resin glycoside







The studies reviewed in this manuscript were supported by grants from CONACyT (CB101380, CB220535) and DGAPA-UNAM (PAPIIT IN212813; IN215016; IN208019). The authors are grateful to Dr Mabel Fragoso-Serrano, and all the graduate students, postdoctoral researchers, and collaborators cited in the references for their significant contributions to this investigation. The authors thank Mr Morris Thompson for essay editing and proofreading of the manuscript. Based on the PhD thesis of coauthor J. Lira-Ricárdez (Posgrado en Ciencias Químicas, UNAM).


  1. Abreu A, McBain A, Simoes M (2012) Plants as sources of new antimicrobials and resistance-modifying agents. Nat Prod Rep 29:1007–1021CrossRefPubMedGoogle Scholar
  2. Achnine L, Pereda-Miranda R, Iglesias-Prieto R, Moreno-Sánchez R, Lotina-Hennsen B (1999) Tricolorin A, a potent natural uncoupler and inhibitor of photosystem ii acceptor side of spinach chloroplasts. Physiol Plant 106:246–252CrossRefGoogle Scholar
  3. Adamson D, Krikstopaityte V, Coote P (2015) Enhanced efficacy of putative efflux pump inhibitor/antibiotic combination treatments versus MDR strains of Pseudomonas aeruginosa in a Galleria mellonella in vivo infection model. J Antimicrob Chemother 70:2271–2278CrossRefPubMedGoogle Scholar
  4. Ayaz M, Subhan F, Sadiq A, Ullah F, Ahmed J, Sewell RD (2017) Cellular efflux transporters and the potential role of natural products in combating efflux mediated drug resistance. Front Biosci 22:732–756CrossRefGoogle Scholar
  5. Bah M, Pereda-Miranda R (1996) Detailed FAB-mass spectrometry and high resolution NMR investigations of tricolorins A-E, individual oligosaccharides from the resins of Ipomoea tricolor (Convolvulaceae). Tetrahedron 52:13063–13080CrossRefGoogle Scholar
  6. Bah M, Pereda-Miranda R (1997) Isolation and structural characterization of new glycolipid ester type dimers from the resins of Ipomoea tricolor (Convolvulaceae). Tetrahedron 53:9007–9022CrossRefGoogle Scholar
  7. Bai LJ, Luo JG, Chen C, Kong LY (2017) Pharesinosides A-G, acylated glycosidic acid methyl esters derivatized by NH2 silica gel on-column catalyzation from the crude resin glycosides of Pharbitis Semen. Tetrahedron 73(20):2863–2871CrossRefGoogle Scholar
  8. Baranova N, Nikaido H (2002) The baeSR two-component regulatory system activates transcription of the yegMNOB (mdtABCD) transporter gene cluster in Escherichia coli and increases its resistance to novobiocin and deoxycholate. J Bacteriol 184:4168–4176CrossRefPubMedPubMedCentralGoogle Scholar
  9. Basha Syed S, Selvaraj Coumar M (2016) P-glycoprotein mediated multidrug resistance reversal by phytochemicals: a review of SAR and future perspective for drug design. Curr Top Med Chem 16(22):2484–2508CrossRefGoogle Scholar
  10. Bautista E, Fragoso-Serrano M, Pereda-Miranda R (2014) Jalapinoside, a macrocyclic bisdesmoside from the resin glycosides of Ipomoea purga, as a modulator of multidrug resistance in human cancer cells. J Nat Prod 78(1):168–172CrossRefPubMedGoogle Scholar
  11. Bautista E, Fragoso-Serrano M, Pereda-Miranda R (2016) Jalapinoside II, a bisdesmoside resin glycoside, and related glycosidic acids from the officinal jalap root (Ipomoea purga). Phytochem Lett 17:85–93CrossRefGoogle Scholar
  12. Bhaskar BV, Babu TMC, Reddy NV, Rajendra W (2016) Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus. Drug Des Dev Ther 10:3237–3252CrossRefGoogle Scholar
  13. Blair JM, Piddock LJ (2016) How to measure export via bacterial multidrug resistance efflux pumps. MBio 7(4):e00840. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13(1):42–51CrossRefPubMedGoogle Scholar
  15. Brito-Arias M, Pereda-Miranda R, Heathcock CH (2004) Synthesis of tricolorin F. J Org Chem 69(14):4567–4570CrossRefPubMedGoogle Scholar
  16. Brown AR, Ettefagh KA, Todd D, Cole PS, Egan JM, Foil DH, Graf TN, Schindler BD, Kaatz GW, Cech NB (2015) A mass spectrometry-based assay for improved quantitative measurements of efflux pump inhibition. PloS One 10:e0124814. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cacciotto P, Ramaswamy VK, Malloci G, Ruggerone P, Vargiu AV (2018) Molecular modeling of multidrug properties of resistance nodulation division (RND) transporters. In: Yamaguchi A, Nishino K (eds) Bacterial multidrug exporters. Methods in molecular biology, vol 1700. Humana Press, New York, pp 179–219CrossRefGoogle Scholar
  18. Cao S, Guza RC, Wisse JH, Miller JS, Evans R, Kingston DG (2005) Ipomoeassins A–E, cytotoxic macrocyclic glycoresins from the leaves of Ipomoea squamosa from the Suriname rainforest. J Nat Prod 68(4):487–492CrossRefPubMedGoogle Scholar
  19. Cao S, Norris A, Wisse JH, Miller JS, Evans R, Kingston DG (2007) Ipomoeassin F, a new cytotoxic macrocyclic glycoresin from the leaves of Ipomoea squamosa from the Suriname rainforest. Nat Prod Res 21(10):872–876CrossRefPubMedPubMedCentralGoogle Scholar
  20. Castañeda-Gómez J, Pereda-Miranda R (2011) Resin glycosides from the herbal drug jalap (Ipomoea purga). J Nat Prod 74(5):1148–1153CrossRefPubMedGoogle Scholar
  21. Castañeda-Gómez J, Figueroa-González G, Jacobo N, Pereda-Miranda R (2013) Purgin II, a resin glycoside ester-type dimer and inhibitor of multidrug efflux pumps from Ipomoea purga. J Nat Prod 76:64–71CrossRefPubMedGoogle Scholar
  22. Castañeda-Gómez J, Rosas-Ramírez D, Cruz-Morales S, Fragoso-Serrano M, Pereda-Miranda R (2017) HPLC-MS profiling of the multidrug-resistance modifying resin glycoside content of Ipomoea alba seeds. Rev Bras Farmacogn 27:434–439CrossRefGoogle Scholar
  23. Castañeda-Gómez J, Lavias-Hernández P, Fragoso-Serrano M, Lorence A, Pereda-Miranda R (2019) Acylsugar diversity in the resin glycosides from Ipomoea tricolor seeds as chemosensitizers in breast cancer cells. Phytochem Lett 32:77–82CrossRefGoogle Scholar
  24. Chandra H, Bishnoi P, Yadav A, Patni B, Mishra AP, Nautiyal AR (2017) Antimicrobial resistance and the alternative resources with special emphasis on plant-based antimicrobials—a review. Plants 6(2):6–16. Google Scholar
  25. Chen L, Li Y, Yu H, Zhang L, Hou T (2012) Computational models for predicting substrates or inhibitors of P-glycoprotein. Drug Discov Today 17(7–8):343–351CrossRefPubMedGoogle Scholar
  26. Chérigo L, Pereda-Miranda R, Fragoso-Serrano M, Jacobo-Herrera N, Kaatz GW, Gibbons S (2008) Inhibitors of bacterial multidrug efflux pumps from the resin glycosides of Ipomoea murucoides. J Nat Prod 71(6):1037–1045CrossRefPubMedGoogle Scholar
  27. Chérigo L, Pereda-Miranda R, Gibbons S (2009) Bacterial resistance modifying tetrasaccharide agents from Ipomoea murucoides. Phytochemistry 70(2):222–227CrossRefPubMedGoogle Scholar
  28. Chiang HY, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, Chorazy ML, Herwaldt LA, Blevins A, Ward MA, Schweizer ML (2017) Incidence and outcomes associated with infections caused by vancomycin-resistant Enterococci in the United States: systematic literature review and meta-analysis. Infect Cont Hosp Ep 38(2):203–215CrossRefGoogle Scholar
  29. Corona-Castañeda B, Pereda-Miranda R (2012) Morning glory resin glycosides as modulators of antibiotic activity in multidrug-resistant Gram-negative bacteria. Planta Med 78:128–131CrossRefPubMedGoogle Scholar
  30. Corona-Castañeda B, Chérigo L, Fragoso-Serrano M, Gibbons S, Pereda-Miranda R (2013) Modulators of antibiotic activity from Ipomoea murucoides. Phytochemistry 95:277–283CrossRefPubMedGoogle Scholar
  31. Corona-Castañeda B, Rosas-Ramírez D, Castañeda-Gómez J, Aparicio-Cuevas MA, Fragoso-Serrano M, Figueroa-González G, Pereda-Miranda R (2016) Resin glycosides from Ipomoea wolcottiana as modulators of the multidrug resistance phenotype in vitro. Phytochemistry 123:48–57CrossRefPubMedGoogle Scholar
  32. Cruz-Morales S, Castañeda-Gómez J, Figueroa-González G, Mendoza-García AD, Lorence A, Pereda-Miranda R (2012) Mammalian multidrug resistance lipopentasaccharide inhibitors from Ipomoea alba seeds. J Nat Prod 75:1603–1611CrossRefPubMedGoogle Scholar
  33. Cruz-Morales S, Castañeda-Gómez J, Rosas-Ramírez D, Fragoso-Serrano M, Figueroa-González G, Lorence A, Pereda-Miranda R (2016) Resin glycosides from Ipomoea alba seeds as potential chemosensitizers in breast carcinoma cells. J Nat Prod 79:3093–3104CrossRefPubMedGoogle Scholar
  34. Desai PV, Sawada GA, Watson IA, Raub TJ (2013) Integration of in silico and in vitro tools for scaffold optimization during drug discovery: predicting P-glycoprotein efflux. Mol Pharmaceutics 10(4):1249–1261CrossRefGoogle Scholar
  35. Dewanjee S, Dua T, Bhattacharjee N, Das A, Gangopadhyay M, Khanra R, Joardar S, Riaz M, Feo V, Zia-Ul-Haq M (2017) Natural products as alternative choices for P-glycoprotein (P-gp) inhibition. Molecules 22(6):871CrossRefPubMedCentralGoogle Scholar
  36. Du D, Wang-Kan X, Neuberger A, van Veen HW, Pos KM, Piddock LJ, Luisi BF (2018) Multidrug efflux pumps: structure, function and regulation. Nat Rev Microbiol 16:523–539CrossRefPubMedGoogle Scholar
  37. Dumont E, Vergalli J, Conraux L, Taillier C, Vassort A, Pajović J, Réfrégiers M, Mourez M, Pagès JM (2018) Antibiotics and efflux: combined spectrofluorimetry and mass spectrometry to evaluate the involvement of concentration and efflux activity in antibiotic intracellular accumulation. J Antimicrob Chemoth 74(1):58–65Google Scholar
  38. Eich E (2008) Solanaceae and Convolvulaceae: secondary metabolites. Springer, BerlinCrossRefGoogle Scholar
  39. Escalante-Sánchez E, Pereda-Miranda R (2007) Batatins I and II, ester-type dimers of acylated pentasaccharides from the resin glycosides of sweet potato. J Nat Prod 70(6):1029–1034CrossRefPubMedGoogle Scholar
  40. Escobedo-Martínez C, Cruz-Morales S, Fragoso-Serrano M, Rahman MM, Gibbons S, Pereda-Miranda R (2010) Characterization of a xylose containing oligosaccharide, an inhibitor of multidrug resistance in Staphylococcus aureus, from Ipomoea pes-caprae. Phytochemistry 71(14–15):1796–1801CrossRefPubMedGoogle Scholar
  41. Fan BY, Gu YC, He Y, Li ZR, Luo JG, Kong LY (2014) Cytotoxic resin glycosides from Ipomoea aquatica and their effects on intracellular Ca2+ concentrations. J Nat Prod 77(10):2264–2272CrossRefPubMedGoogle Scholar
  42. Fan BY, Li ZR, Ma T, Gu YC, Zhao H, Luo JG, Kong LY (2015) Further screening of the resin glycosides in the edible water spinach and characterisation on their mechanism of anticancer potential. J Funct Food 19:141–154CrossRefGoogle Scholar
  43. Figueroa-González G, Jacobo-Herrera N, Zentella-Dehesa A, Pereda-Miranda R (2012) Reversal of multidrug resistance by morning glory resin glycosides in human breast cancer cells. J Nat Prod 75:93–97CrossRefPubMedGoogle Scholar
  44. Govindarajan M (2018) Amphiphilic glycoconjugates as potential anti-cancer chemotherapeutics. Eur J Med Chem 143:1208–1253CrossRefPubMedGoogle Scholar
  45. Haynes MK, Garcia M, Peters R, Waller A, Tedesco P, Ursu O, Bologa CG, Santos RG, Pinilla C, Wu TH, Lovchik JA, Oprea TI, Sklar LA, Tegos GP (2018) High-throughput flow cytometry screening of multidrug efflux systems. In: Yamaguchi A, Nishino K (eds) Bacterial multidrug exporters. Methods in molecular biology, vol 1700. Humana Press, New York, pp 293–318CrossRefGoogle Scholar
  46. Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8(1):67–113CrossRefPubMedGoogle Scholar
  47. Kaatz GW, Moudgal VV, Seo SM (2002) Identification and characterization of a novel efflux-related multidrug resistance phenotype in Staphylococcus aureus. J Antimicrob Chemother 50:833–838CrossRefPubMedGoogle Scholar
  48. Kathawala RJ, Gupta P, Ashby CR Jr, Chen ZS (2015) The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Update 18:1–17CrossRefGoogle Scholar
  49. Kroumova AB, Zaitlin D, Wagner GJ (2016) Natural variability in acyl moieties of sugar esters produced by certain tobacco and other Solanaceae species. Phytochemistry 130:218–227CrossRefPubMedGoogle Scholar
  50. Lamut A, Peterlin Mašič L, Kikelj D, Tomašič T (2019) Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Med Res Rev. PubMedGoogle Scholar
  51. Leckie BM, D’Ambrosio DA, Chappell TM, Halitschke R, De Jong DM, Kessler A, Kennedy GG, Mutschler MA (2016) Differential and synergistic functionality of acylsugars in suppressing oviposition by insect herbivores. PLoS One. PubMedPubMedCentralGoogle Scholar
  52. Liu X, Enright M, Barry CS, Jones AD (2017) Profiling, isolation and structure elucidation of specialized acylsucrose metabolites accumulating in trichomes of Petunia species. Metabolomics 13:85. CrossRefGoogle Scholar
  53. Locher KP (2016) Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat Struct Mol Biol 23:487–493CrossRefPubMedGoogle Scholar
  54. Lomovskaya O, Watkins W (2001) Inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria. J Mol Microb Biotech 3:225–236Google Scholar
  55. Lotina-Hennsen B, King-Díaz B, Pereda-Miranda R (2013) Tricolorin A as a natural herbicide. Molecules 18:778–788CrossRefPubMedPubMedCentralGoogle Scholar
  56. Luu VT, Weinhold A, Ullah C, Dressel S, Schoettner M, Gase K, Gaquerel E, Xu S, Baldwin IT (2017) O-acyl sugars protect a wild tobacco from both native fungal pathogens and a specialist herbivore. Plant Physiol 174:370–386CrossRefPubMedPubMedCentralGoogle Scholar
  57. Mahmood HY, Jamshidi S, Sutton JM, Rahman KM (2016) Current advances in developing inhibitors of bacterial multidrug efflux pumps. Curr Med Chem 23(10):1062–1081CrossRefPubMedPubMedCentralGoogle Scholar
  58. Moghe GD, Leong BJ, Hurney SM, Jones AD, Last RL (2017) Evolutionary routes to biochemical innovation revealed by integrative analysis of a plant-defense related specialized metabolic pathway. Elife 6:e28468. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Nagano T, Pospíšil J, Chollet G, Schulthoff S, Hickmann V, Moulin E, Herrmann J, Müller R, Fürstner A (2009) Total synthesis and biological evaluation of the cytotoxic resin glycosides ipomoeassin A-F and analogues. Chem-Eur J 15(38):9697–9706CrossRefPubMedGoogle Scholar
  60. Nascimento E, Vitali LH, Kress MRVZ, Martinez R (2017) Cryptococcus neoformans and C. gattii isolates from both HIV-infected and uninfected patients: antifungal susceptibility and outcome of cryptococcal disease. Rev Inst Med Trop SP. Google Scholar
  61. Nikaido H, Pagès JM (2012) Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol Rev 36(2):340–363CrossRefPubMedGoogle Scholar
  62. O’Driscoll T, Crank CW (2015) Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist 8:217–230PubMedPubMedCentralGoogle Scholar
  63. Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S, Iwasaku K, Nakayama SI, Kitawaki J, Unemo M (2011) Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea? Detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother 55(7):3538–3545CrossRefPubMedPubMedCentralGoogle Scholar
  64. Ono M (2017) Resin glycosides from Convolvulaceae plants. J Nat Med 71(4):591–604CrossRefPubMedGoogle Scholar
  65. Pendleton JN, Gorman SP, Gilmore BF (2013) Clinical relevance of the ESKAPE pathogens. Expert Rev Anti-Infect Ther 11(3):297–308CrossRefPubMedGoogle Scholar
  66. Pereda-Miranda R, Bah M (2003) Biodynamic constituents in the Mexican morning glories: purgative remedies transcending boundaries. Curr Top Med Chem 3(2):111–131CrossRefPubMedGoogle Scholar
  67. Pereda-Miranda R, Hernández-Carlos B (2002) HPLC Isolation and structural elucidation of diastereomeric niloyl ester tetrasaccharides from Mexican scammony root. Tetrahedron 58:3145–3154CrossRefGoogle Scholar
  68. Pereda-Miranda R, Mata R, Anaya AL, Wickramaratne DM, Pezzuto JM, Kinghorn AD (1993) Tricolorin A, major phytogrowth inhibitor from Ipomoea tricolor. J Nat Prod 56:571–582CrossRefPubMedGoogle Scholar
  69. Pereda-Miranda R, Escalante-Sánchez E, Escobedo-Martínez C (2005) Characterization of lipophilic pentasaccharides from beach morning glory (Ipomoea pes-caprae). J Nat Prod 68:226–230CrossRefPubMedGoogle Scholar
  70. Pereda-Miranda R, Kaatz GW, Gibbons S (2006) Polyacylated oligosaccharides from medicinal Mexican morning glory species as antibacterials and inhibitors of multidrug resistance in Staphylococcus aureus. J Nat Prod 69(3):406–409CrossRefPubMedGoogle Scholar
  71. Pereda-Miranda R, Villatoro-Vera R, Bah M, Lorence A (2009) Pore-forming activity of morning glory resin glycosides in model membranes. Rev Latinoamer Quim 37:144–154Google Scholar
  72. Pereda-Miranda R, Rosas-Ramírez D, Castañeda-Gómez J (2010) Resin glycosides from the morning glory family. In: Kinghorn A, Falk H, Kobayashi J (eds) Progress in the chemistry of organic natural products, vol 92. Springer, New York, pp 77–153Google Scholar
  73. Prasch S, Bucar F (2015) Plant derived inhibitors of bacterial efflux pumps: an update. Phytochem Rev 14(6):961–974CrossRefGoogle Scholar
  74. Prestegard JH, Liu J, Widmalm G (2017) Oligosaccharides and polysaccharides. In: Varki A, Cummings RD, Esko JD et al (eds) Essentials of glycobiology, 3rd edn. Cold Spring Harbor Laboratory Press, New YorkGoogle Scholar
  75. Ramaswamy VK, Cacciotto P, Malloci G, Vargiu AV, Ruggerone P (2017) Computational modelling of efflux pumps and their inhibitors. Essays Biochem 61(1):141–156CrossRefPubMedGoogle Scholar
  76. Rao M, Padyana S, Dipin KM, Kumar S, Nayak BB, Varela MF (2018) Antimicrobial compounds of plant origin as efflux pump inhibitors: new avenues for controlling multidrug resistant pathogens. J Antimicrob Agents 4:159. Google Scholar
  77. Remschmidt C, Schneider S, Meyer E, Schroeren-Boersch B, Gastmeier P, Schwab F (2017) Surveillance of antibiotic use and resistance in intensive care units (SARI): a 15-year cohort study. Dtsch Arztebl Int 114(50):858–865PubMedPubMedCentralGoogle Scholar
  78. Rencurosi A, Mitchell EP, Cioci G, Pérez S, Pereda-Miranda R, Imberty A (2004) Crystal structure of tricolorin A: molecular rationale for the biological properties of resin glycosides found in some Mexican herbal remedies. Angew Chem Int Edit 43(44):5918–5922CrossRefGoogle Scholar
  79. Rivero-Cruz I, Acevedo L, Guerrero JA, Martínez S, Pereda-Miranda R, Mata R, Bye R, Franzblau S, Timmermann BN (2005) Antimycobacterial agents from selected Mexican medicinal plants. J Pharm Pharmacol 57(9):1117–1126CrossRefPubMedGoogle Scholar
  80. Rodriguez J, O’Neill S, Walczak MA (2018) Constrained saccharides: a review of structure, biology, and synthesis. Nat Prod Rep 35(3):220–229CrossRefPubMedGoogle Scholar
  81. Rosas-Ramírez D, Escalante-Sánchez E, Pereda-Miranda R (2011) Batatins III-VI, glycolipid ester-type dimers from Ipomoea batatas. Phytochemistry 72:773–780CrossRefPubMedGoogle Scholar
  82. Rosas-Ramírez D, Escandón-Rivera S, Pereda-Miranda R (2018) Morning glory resin glycosides as α-glucosidase inhibitors: in vitro and in silico analysis. Phytochemistry 148:39–47CrossRefPubMedGoogle Scholar
  83. Schepetkin IA, Quinn MT (2006) Botanical polysaccharides: macrophage immunomodulation and therapeutic potential. Int Immunopharmacol 6(3):317–333CrossRefPubMedGoogle Scholar
  84. Schillaci D, Spanò V, Parrino B, Carbone A, Montalbano A, Barraja P, Diana P, Cirrincione G, Cascioferro S (2017) Pharmaceutical approaches to target antibiotic resistance mechanisms. J Med Chem 60(20):8268–8297CrossRefPubMedGoogle Scholar
  85. Silva R, Vilas-Boas V, Carmo H, Dinis-Oliveira RJ, Carvalho F, de Lourdes Bastos M, Remião F (2015) Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy. Pharmacol Therapeut 149:1–123CrossRefGoogle Scholar
  86. Spengler G, Kincses A, Gajdács M, Amaral L (2017) New roads leading to old destinations: efflux pumps as targets to reverse multidrug resistance in bacteria. Molecules 22(3):468. CrossRefPubMedCentralGoogle Scholar
  87. Stavri M, Piddock LJ, Gibbons S (2007) Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemoth 59(6):1247–1260CrossRefGoogle Scholar
  88. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K (2000) Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA 97(4):1433–1437CrossRefGoogle Scholar
  89. Sun J, Deng Z, Yan A (2014) Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Bioph Res Co 453:254–267CrossRefGoogle Scholar
  90. Szakács G, Hall MD, Gottesman MM, Boumendjel A, Kachadourian R, Day BJ, Baubichon-Cortay H, Di Pietro A (2014) Targeting the Achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance. Chem Rev 114(11):5753–5774CrossRefPubMedPubMedCentralGoogle Scholar
  91. Tegos G, Stermitz FR, Lomovskaya O, Lewis K (2002) Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials. Antimicrob Agents Ch 46(10):3133–3141CrossRefGoogle Scholar
  92. Thai KM, Ngo TD, Phan TV, Tran TD, Nguyen NV, Nguyen TH, Le MT (2015) Virtual screening for novel Staphylococcus aureus NorA efflux pump inhibitors from natural products. Med Chem 11(2):135–155CrossRefPubMedGoogle Scholar
  93. Varela MF, Andersen JL, Ranjana KC, Kumar S, Sanford LM, Hernandez AJ (2017) Bacterial resistance mechanisms and inhibitors of multidrug efflux pumps belonging to the major facilitator superfamily of solute transport systems. In: Rahman A, Choudhary MI (eds) Frontiers in anti-infective drug discovery, vol 5. Bentham Science Publishers, Sharjah, p 109Google Scholar
  94. Venter H, Mowla R, Ohene-Agyei T, Ma S (2015) RND-type drug efflux pumps from Gram-negative bacteria: molecular mechanism and inhibition. Front Microbiol. PubMedPubMedCentralGoogle Scholar
  95. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116CrossRefPubMedGoogle Scholar
  96. Volpe DA, Qosa H (2018) Challenges with the precise prediction of ABC-transporter interactions for improved drug discovery. Expert Opin Drug Dis 13(8):697–707CrossRefGoogle Scholar
  97. Yu Y, Shen M, Song Q, Xie J (2018) Biological activities and pharmaceutical applications of polysaccharide from natural resources: a review. Carbohydr Polym 183:91–101CrossRefPubMedGoogle Scholar
  98. Zhu D, Chen C, Bai L, Kong L, Luo J (2019a) Downregulation of aquaporin 3 mediated the laxative effect in the rat colon by a purified resin glycoside fraction from Pharbitis Semen. Evid-Based Compl Alt. Google Scholar
  99. Zhu D, Chen C, Xia Y, Kong LY, Luo J (2019b) A purified resin glycoside fraction from Pharbitidis Semen induces paraptosis by activating chloride intracellular channel-1 in human colon cancer cells. Integr Cancer Ther 18(1):1–13Google Scholar
  100. Zong G, Shi WQ (2017) Total synthesis of ipomoeassin F and its analogs for biomedical research. In: Harmata M (ed) Strategies and tactics in organic synthesis, vol 13. Academic Press, Cambridge, p 81Google Scholar
  101. Zong G, Aljewari H, Hu Z, Shi WQ (2016) Revealing the pharmacophore of ipomoeassin F through molecular editing. Org Lett 18(7):1674–1677CrossRefPubMedPubMedCentralGoogle Scholar
  102. Zong G, Whisenhunt L, Hu Z, Shi WQ (2017) Synergistic contribution of tiglate and cinnamate to cytotoxicity of ipomoeassin F. J Org Chem 82(9):4977–4985CrossRefPubMedPubMedCentralGoogle Scholar
  103. Zong G, Sun X, Bhakta R, Whisenhunt L, Hu Z, Wang F, Shi WQ (2018) New insights into structure-activity relationship of ipomoeassin F from its bioisosteric 5-oxa/aza analogues. Eur J Med Chem 144:751–757CrossRefPubMedGoogle Scholar
  104. Zong G, Hu Z, O’Keefe S, Tranter D, Iannotti MJ, Baron L, Hall B, Corfield K, Paatero AO, Henderson MJ, Roboti P, Zhou J, Sun X, Govindarajan M, Rohde JM, Blanchard N, Simmonds R, Inglese J, Du Y, Demangel C, High S, Paavilainen VO, Shi WQ (2019) Ipomoeassin F binds Sec61α to inhibit protein translocation. J Am Chem Soc 141(21):8450–8461CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Departamento de Farmacia, Facultad de Química, and Programa de Maestría y Doctorado en Ciencias QuímicaUniversidad Nacional Autónoma de México, Ciudad UniversitariaMexico CityMexico

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