A desirable attribute of novel antimicrobial agents for bacterial diarrhea is decreased toxicity toward host intestinal microbiota. In addition, gut dysbiosis is associated with an increased risk of developing intestinal cancer. In this study, the selective growth-inhibitory activities of ten phytochemicals and their synthetic analogs (berberine, bismuth subsalicylate, ferron, 8-hydroxyquinoline, chloroxine, nitroxoline, salicylic acid, sanguinarine, tannic acid, and zinc pyrithione), as well as those of six commercial antibiotics (ceftriaxone, ciprofloxacin, chloramphenicol, metronidazole, tetracycline, and vancomycin) against 21 intestinal pathogenic/probiotic (e.g., Salmonella spp. and bifidobacteria) bacterial strains and three intestinal cancer/normal (Caco-2, HT29, and FHs 74 Int) cell lines were examined in vitro using the broth microdilution method and thiazolyl blue tetrazolium bromide assay. Chloroxine, ciprofloxacin, nitroxoline, tetracycline, and zinc pyrithione exhibited the most potent selective growth-inhibitory activity against pathogens, whereas 8-hydroxyquinoline, chloroxine, nitroxoline, sanguinarine, and zinc pyrithione exhibited the highest cytotoxic activity against cancer cells. None of the tested antibiotics were cytotoxic to normal cells, whereas 8-hydroxyquinoline and sanguinarine exhibited selective antiproliferative activity against cancer cells. These findings indicate that 8-hydroxyquinoline alkaloids and metal-pyridine derivative complexes are chemical structures derived from plants with potential bioactive properties in terms of selective antibacterial and anticancer activities against diarrheagenic bacteria and intestinal cancer cells.

Department of Crop Sciences and Agroforestry Faculty of Tropical AgriSciences Czech University of Life Sciences Prague Kamycka 129 16500 Praha Suchdol Czech Republic

Department of Microbiology Nutrition and Dietetics Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences Prague Kamycka 129 16500 Praha Suchdol Czech Republic

Department of Zoology and Fisheries Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences Prague Kamycka 129 16500 Praha Suchdol Czech Republic

Zobrazit více v PubMed

World Health Organization Diarrhoeal Disease. [(accessed on 19 March 2020)]; Available online: https://www.who.int/en/news-room/fact-sheets/detail/diarrhoeal-disease.

Garrett W.S. The gut microbiota and colon cancer. Science. 2019;364:1133–1135. doi: 10.1126/science.aaw2367. PubMed DOI

Diniz-Santos D.R., Silva L.R., Silva N. Antibiotics for the empirical treatment of acute infectious diarrhea in children. Braz. J. Infect. Dis. 2006;10:217–227. doi: 10.1590/S1413-86702006000300011. PubMed DOI

White N.J. Qinghaosu (Artemisinin): The Price of Success. Science. 2008;320:330–334. doi: 10.1126/science.1155165. PubMed DOI

Formiga R.D.O., Quirino Z.G.M., Diniz M.D.F.F.M., Marinho A.F., Tavares J.F., Batista L. Maytenus Erythroxylon Reissek (Celastraceae) ethanol extract presents antidiarrheal activity via antimotility and antisecretory mechanisms. World J. Gastroenterol. 2017;23:4381–4389. doi: 10.3748/wjg.v23.i24.4381. PubMed DOI PMC

Hao D.C., Xiao P.G. Pharmaceutical resource discovery from traditional medicinal plants: Pharmacophylogeny and pharmacophylogenomics. Chin. Herb. Med. 2020;12:104–117. doi: 10.1016/j.chmed.2020.03.002. PubMed DOI PMC

Kokoska L., Kloucek P., Leuner O., Novy P. Plant-Derived Products as Antibacterial and Antifungal Agents in Human Health Care. Curr. Med. Chem. 2019;26:5501–5541. doi: 10.2174/0929867325666180831144344. PubMed DOI

Sun F., Zhang Q., Zhao J., Zhang H., Zhai Q., Chen W. A potential species of next-generation probiotics? The dark and light sides of Bacteroides fragilis in health. Food Res. Int. 2019;126:108590. doi: 10.1016/j.foodres.2019.108590. PubMed DOI

Behnsen J., Deriu E., Sassone-Corsi M., Raffatellu M. Probiotics: Properties, Examples, and Specific Applications. Cold Spring Harb. Perspect. Med. 2013;3:a010074. doi: 10.1101/cshperspect.a010074. PubMed DOI PMC

Novakova J., Vlkova E., Bonusova B., Rada V., Kokoska L. In vitro selective inhibitory effect of 8-hydroxyquinoline against bifidoba cteria and clostridia. Anaerobe. 2013;22:134–136. doi: 10.1016/j.anaerobe.2013.05.008. PubMed DOI

WikiZero: Chloroxine. [(accessed on 10 August 2020)]; Available online: https:// wikizero.com/en/Chloroxine.

Bruneau A., Baylatry M.T., Joly A.C., Sokol H. Gut microbiota: What impact on colorectal carcinogenesis and treatment? Bull. Cancer. 2018;105:70–80. doi: 10.1016/j.bulcan.2017.10.025. PubMed DOI

Sambruy Y., Ferruzza S., Ranaldi G., De Angelis I. Intestinal cell culture models: Applications in toxicology and pharmacology. Cell Biol. Toxicol. 2001;17:301–317. doi: 10.1023/A:1012533316609. PubMed DOI

Elsea S.H., Osheroff N., Nitiss J.L. Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase-II as the primary cellular target for the quinolone CP-115,953 in yeast. J. Biol. Chem. 1992;267:13150–13153. PubMed

Oliphant C.M., Green G.M. Quinolones: A comprehensive review. Am. Fam. Physician. 2002;65:455–464. PubMed

Bourikas L.A., Kolios G., Valatas V., Notas G., Drygiannakis I., Pelagiadis I., Manousou P., Klironomos S., A Mouzas I., Kouroumalis E. Ciprofloxacin decreases survival in HT-29 cells via the induction of TGF-β1 secretion and enhances the anti-proliferative effect of 5-fluorouracil. Br. J. Pharmacol. 2009;157:362–370. doi: 10.1111/j.1476-5381.2009.00161.x. PubMed DOI PMC

Zeng X.H., Li Y.H., Wu S.S., Hao R.L., Li H., Ni H., Han H.B., Lin L. New and Highly Efficient Column Chromatographic Extraction and Simple Purification of Camptothecin from Camptotheca acuminata and Nothapodytes pittosporoides. Phytochem. Anal. 2013;24:623–630. doi: 10.1002/pca.2441. PubMed DOI

Arafa R.K., Hegazy G.H., Piazza G., Abadi A.H. Synthesis and in vitro antiproliferative effect of novel quinoline-based potential anticancer agents. Eur. J. Med. Chem. 2013;63:826–832. doi: 10.1016/j.ejmech.2013.03.008. PubMed DOI

Slaninova I., Pencikova K., Urbanova J., Slanina J., Taborska E. Antitumour activities of sanguinarine and related alkaloids. Phytochem. Rev. 2013;13:51–68. doi: 10.1007/s11101-013-9290-8. DOI

Khalifa N., Eweas A., Al-Omar M.A., Hozzein W.N. Synthesis and antimicrobial activity of some novel 8-hydroxy-7-iodoquinoline-5-sulfonamide derivatives. J. Pure Appl. Microbiol. 2014;8:629–637.

Kos J., Mitrovic A. Nitroxoline: Repurposing its antimicrobial to antitumor application. Acta Biochim. Pol. 2019:521–531. doi: 10.18388/abp.2019_2904. PubMed DOI

Zhao C., Chen X., Yang C., Zang D., Lan X., Liao S., Zhang P., Wu J., Li X., Liu N., et al. Repurposing an antidandruff agent to treating cancer: Zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases. Oncotarget. 2017;8:13942–13956. doi: 10.18632/oncotarget.14572. PubMed DOI PMC

Merriam C.V., Citron D.M., Tyrrell K.L., Warren Y.A., Goldstein E.J. In vitro activity of azithromycin and nine comparator agents against 296 strains of oral anaerobes and 31 strains of Eikenella corrodens. Int. J. Antimicrob. Agents. 2006;28:244–248. doi: 10.1016/j.ijantimicag.2006.03.028. PubMed DOI

Kheadr E., Bernoussi N., Lacroix C., Fliss I. Comparison of the sensitivity of commercial strains and infant isolates of bifidobacteria to antibiotics and bacteriocins. Int. Dairy J. 2004;14:1041–1053. doi: 10.1016/j.idairyj.2004.04.010. DOI

Moubareck C.A., Gavini F., Vaugien L., Butel M.J., Doucet-Populaire F. Antimicrobial susceptibility of bifidobacteria. J. Antimicrob. Chemother. 2005;55:38–44. doi: 10.1093/jac/dkh495. PubMed DOI

Sharma R., Park T.E., Moy S. Ceftazidime-Avibactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination for the Treatment of Resistant Gram-negative Organisms. Clin. Ther. 2016;38:431–444. doi: 10.1016/j.clinthera.2016.01.018. PubMed DOI

Novakova J., Dzunkova M., Musilova S., Vlkova E., Kokoska L., Moya A., D’Auria G., Unkova M.D. Selective growth-inhibitory effect of 8-hydroxyquinoline towards Clostridium difficile and Bifidobacterium longum subsp. longum in co-culture analysed by flow cytometry. J. Med. Microbiol. 2014;63:1663–1669. doi: 10.1099/jmm.0.080796-0. PubMed DOI

Novakova J., Vlkova E., Salmonova H., Pechar R., Rada V., Kokoska L. Anticlostridial agent 8-hydroxyquinoline improves the isolation of faecal bifidobacteria on modified Wilkins-Chalgren agar with mupirocin. Lett. Appl. Microbiol. 2016;62:330–335. doi: 10.1111/lam.12552. PubMed DOI

Skrivanova E., Van Immerseel F., Hovorkova P., Kokoska L. In Vitro Selective Growth-Inhibitory Effect of 8-Hydroxyquinoline on Clostridium perfringens versus Bifidobacteria in a Medium Containing Chicken Ileal Digesta. PLoS ONE. 2016;11:e0167638. doi: 10.1371/journal.pone.0167638. PubMed DOI PMC

Kim Y.M., Jeong E.Y., Lim J.H., Lee H.S. Antimicrobial effects of 8-quinolinol. J. Food Sci. Biotechnol. 2006;15:817–819.

Prapasarakul N., Tummaruk P., Niyomtum W., Tripipat T., Serichantalergs O. Virulence Genes and Antimicrobial Susceptibilities of Hemolytic and Nonhemolytic Escherichia coli Isolated from Post-Weaning Piglets in Central Thailand. J. Vet. Med. Sci. 2010;72:1603–1608. doi: 10.1292/jvms.10-0124. PubMed DOI

Tranter R.W. The in vitro activity of halquinol against Vibrio cholerae. J. Trop. Med. Hyg. 1968;71:146–149. PubMed

Sobke A., Makarewicz O., Baier M., Bar C., Pfister W., Gatermann S., Pletz M., Forstner C. Empirical treatment of lower urinary tract infections in the face of spreading multidrug resistance: In vitro study on the effectiveness of nitroxoline. Int. J. Antimicrob. Agents. 2018;51:213–220. doi: 10.1016/j.ijantimicag.2017.10.010. PubMed DOI

Chandler C.J., Segel I.H. Mechanism of the Antimicrobial Action of Pyrithione: Effects on Membrane Transport, ATP Levels, and Protein Synthesis. Antimicrob. Agents Chemother. 1978;14:60–68. doi: 10.1128/AAC.14.1.60. PubMed DOI PMC

Lahiri S.C., Dutta N.K. Berberine and chloramphenicol in the treatment of cholera and severe diarrhoea. J. Indian Med. Assoc. 1967;48:1–11. PubMed

Sack R.B., Froehlich J.L. Berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins. Infect. Immun. 1982;35:471–475. doi: 10.1128/IAI.35.2.471-475.1982. PubMed DOI PMC

Hamoud R., Reichling J., Wink M.R. Synergistic antibacterial activity of the combination of the alkaloid sanguinarine with EDTA and the antibiotic streptomycin against multidrug resistant bacteria. J. Pharm. Pharmacol. 2014;67:264–273. doi: 10.1111/jphp.12326. PubMed DOI

Chukwudi C.U. rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines. Antimicrob. Agents Chemother. 2016;60:4433–4441. doi: 10.1128/AAC.00594-16. PubMed DOI PMC

Hu D., Han Z., Li C., Lv L., Cheng Z., Liu S. Florfenicol induces more severe hemotoxicity and immunotoxicity than equal doses of chloramphenicol and thiamphenicol in Kunming mice. Immunopharmacol. Immunotoxicol. 2016;38:472–485. doi: 10.1080/08923973.2016.1247853. PubMed DOI

Onoda T., Ono T., Dhar D.K., Yamanoi A., Nagasue N. Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells. Int. J. Cancer. 2005;118:1309–1315. doi: 10.1002/ijc.21447. PubMed DOI

Dewdney J.M. Effects of beta-lactam antibiotics on eukaryotic cells. Cell Boil. Toxicol. 1986;2:509–511. doi: 10.1007/BF00117852. PubMed DOI

Eisenstein B.I., Schaechter M. DNA and Chromosome Mechanics. In: Schaechter M., Engleberg N.C., DiRita V.J., editors. Schaechter’s Mechanisms of Microbial Disease. Lippincott Williams & Wilkins; Philadelphia, PA, USA: 2007. p. 28.

Hanaki H., Kuwahara-Arai K., Boyle-Vavra S., Daum R.S., Labischinski H., Hiramatsu K. Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant Staphylococcus aureus clinical strains Mu3 and Mu50. J. Antimicrob. Chemother. 1998;42:199–209. doi: 10.1093/jac/42.2.199. PubMed DOI

Oliveri V., Vecchio G. 8-Hydroxyquinolines in medicinal chemistry: A structural perspective. Eur. J. Med. Chem. 2016;120:252–274. doi: 10.1016/j.ejmech.2016.05.007. PubMed DOI

Freitas L.B.D.O., Borgati T.F., Gil R.F., Ruiz A., Marchetti G.M., De Carvalho J.E., Da Cunha E.F., Ramalho T.D.C., Alves R.B. Synthesis and antiproliferative activity of 8-hydroxyquinoline derivatives containing a 1,2,3-triazole moiety. Eur. J. Med. Chem. 2014;84:595–604. doi: 10.1016/j.ejmech.2014.07.061. PubMed DOI

Lazar V., Ditu L.-M., Pircalabioru G.G., Gheorghe I., Curutiu C., Holban A.M., Picu A., Petcu L., Chifiriuc M.C. Aspects of Gut Microbiota and Immune System Interactions in Infectious Diseases, Immunopathology, and Cancer. Front. Immunol. 2018;9:1830. doi: 10.3389/fimmu.2018.01830. PubMed DOI PMC

Rajkovic A., Jovanovic J., Monteiro S., Decleer M., Andjelkovic M., Foubert A., Beloglazova N., Tsilla V., Sas B., Madder A., et al. Detection of toxins involved in foodborne diseases caused by Gram-positive bacteria. Compr. Rev. Food Sci. Food Saf. 2020;19:1605–1657. doi: 10.1111/1541-4337.12571. PubMed DOI

Clinical and Laboratory Standards Institute . Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 3rd ed. Clinical and Laboratory Standards Institute; Wayne, PA, USA: 2015. Approved Standard.

Hecht D.W. Antimicrobial agents and susceptibility testing: Susceptibility testing of anaerobic bacteria. In: Murray P.R., Baron E.J., Pfaller M.A., Tenover F.C., Yolken R.H., editors. Manual of Clinical Microbiology. 7th ed. ASM Press; Washington, DC, USA: 1999. pp. 1555–1562.

Houdkova M., Rondevaldova J., Doskocil I., Kokoska L. Evaluation of antibacterial potential and toxicity of plant volatile compounds using new broth microdilution volatilization method and modified MTT assay. Fitoterapia. 2017;118:56–62. doi: 10.1016/j.fitote.2017.02.008. PubMed DOI

Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods. 1983;65:55–63. doi: 10.1016/0022-1759(83)90303-4. PubMed DOI

Houdkova M., Urbanova K., Doskocil I., Rondevaldova J., Novy P., Nguon S., Chrun R., Kokoska L. In vitro growth-inhibitory effect of Cambodian essential oils against pneumonia causing bacteria in liquid and vapour phase and their toxicity to lung fibroblasts. S. Afr. J. Bot. 2018;118:85–97. doi: 10.1016/j.sajb.2018.06.005. DOI

TIBCO Software Inc Statistica, Data Analysis Software System, Version 13.0. [(accessed on 30 September 2017)]; Available online: http://statistica.io.

Evaluation of In Vitro Synergistic Effects of Tetracycline with Alkaloid-Related Compounds against Diarrhoeic Bacteria

In Vitro Selective Combinatory Effect of Ciprofloxacin with Nitroxoline, Sanguinarine, and Zinc Pyrithione against Diarrhea-Causing and Gut Beneficial Bacteria

In Vitro Selective Antibacterial and Antiproliferative Effects of Ethanolic Extracts from Cambodian and Philippine Plants Used in Folk Medicine for Diarrhea Treatment