European Review for Medical and Pharmacological Sciences 2019; 23: 7135-7143 Antimicrobial properties of the medicinal plant Cardiospermum halicacabum L: new evidence and future perspectives R. GAZIANO1, E. CAMPIONE2, F. IACOVELLI3, E.S. PISTOIA1, D. MARINO1, M. MILANI4, P. DI FRANCESCO1, F. PICA1, L. BIANCHI2, A. ORLANDI5, S. MARSICO6, M. FALCONI3, S. AQUARO6 1Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy 2Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy 3Department of Biology, Structural Bioinformatics Group, University of Rome Tor Vergata, Rome, Italy 4Department Cantabria Labs Difa Cooper, Caronno Pertusella, Varese, Italy 5Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy 6Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, Rende, Cosenza, Italy Roberta Gaziano and Elena Campione contributed equally to this work and should be considered co-first authors Key Words: Abstract. – The emergence and rapid spread of multidrug-resistance in human pathogenic C. halicacabum, Antimicrobial, T. rubrum, Hsp90, microorganisms urgently require the develop- Molecular modeling, Antifungal therapeutic strate- ment of novel therapeutic strategies for the gies. treatment of infectious diseases. From this per- spective, the antimicrobial properties of the nat- ural plant-derived products may represent an Introduction important alternative therapeutic option to syn- thetic drugs. Among medicinal plants, the Car- diospermum halicacabum L. (C. halicacabum), The increasing resistance of the microorgan- belonging to Sapindaceae family, could be a isms towards conventional antimicrobial agents very promising candidate for its antimicrobial has led to serious health problems in recent years activity against a wide range of microorganisms, and even more it is be expected in the future. This including both Gram positive and Gram nega- global phenomenon encourages the development tive bacteria, as well as fungal pathogens. Al- of new agents which can effectively inhibit mi- though the antimicrobial properties of C. halica- cabum have been intensively studied, the mech- crobial growth. An alternative and very promis- anism/s by which it exerts the inhibitory activi- ing approach to overcome this issue might be the ty towards the pathogenic microbes have not yet use of natural antimicrobial products. The Middle been completely understood. This review focus- East represents an important source of medicinal es on the main antimicrobial activities displayed plants, which have been used for treating diseases in vitro by the plant extract, with particular at- for thousands of years in traditional medicine. tention on our recent advances. We demonstrat- The bioactive aromatic products extracted from ed that C. halicacabum is able to exert in vitro a some of these plants have been shown to possess dose-dependent fungistatic effect against Try- 1 chophyton rubrum (T. rubrum) through molecu- potential antimicrobial properties . Nowadays lar interaction with the fungal heat shock protein people in developing countries prefer plant-de- (Hsp)-90 chaperone. These findings are sup- rived natural products limiting their exposure to ported by a growing body of research indicating the side effects and toxicity of synthetic drugs. the crucial role played by the Hsp90 in the viru- Among medicinal plants, Cardiospermum hali- lence of the pathogenic microorganisms, includ- ing fungal pathogens. The possible future use of cacabum L. (C. halicacabum) is an herbaceous C. halicacabum for treating a wide range of in- climber belonging to the Sapindaceae family, fectious diseases is also discussed. naturally distributed in tropical and subtropical Corresponding Author: Mattia Falconi, Ph.D; e-mail: [email protected] 7135 R. Gaziano, E. Campione, F. Iacovelli, E.S. Pistoia, D. Marino, et al. regions of the world. It grows in the plains of action of its bioactive compounds with the fungal Africa, America, Bangladesh, India, Malacca, Hsp90, compromising the biological functions and Pakistan. Its roots, leaves, and seeds have of the chaperone24. These findings are support- been employed as herbal medication2. The phy- ed by recent reports demonstrating the pivotal tochemical characterization of the constituents of role played by the Hsp90 in the virulence of the the plant extracts revealed the presence of β-ara- pathogenic microorganisms like bacteria, fungi, chidic acid, apigenin, apigenin-7-O-glucuronide, and human protozoan. Based on our results, here- and chrysoeriol-7-O-glucuronide3,4. Various fatty in we firstly propose that the chaperone Hsp90 acids and volatile esters were also isolated from in pathogens could be a potential therapeutic seed oil5,6. Furthermore, other secondary me- target for C. halicacabum, defining a possible tabolites have been found in small quantities in mechanism of action underlying its antimicrobial the extracts including alkaloids, carbohydrates, properties. Finally, the future therapeutic utility proteins, saponins, lignin, steroids, flavonoids, of this herb in the treatment of infectious diseases terpenoids, and cardiac glycosides7,8. The plant- is also discussed. based herbal products are commercially avail- able as a gel, cream, shampoo, spray, medical drops, and pills. They are effective especially Antimicrobial Properties of in the treatment of dry itchy skin and scalp and Cardiospermum Halicacabum for treating chronic skin inflammatory disorders, including psoriasis4,9. The plant has been used in Antibacterial Activity Ayurveda and folk medicine for a long time in It has been reported that Cardiospermum the treatment of rheumatism, lumbago, cough, halicacabum exerts an important antimicrobial and hyperthermia10. Furthermore, it has been em- activity against numerous bacteria responsible ployed to treat nervous diseases like epilepsy and for the most common human infectious diseases. anxiety disorders, as a demulcent in orchitis, and Depending on the different solvents or extraction in dropsy11-13. C. halicacabum also acts as a dia- techniques, a different degree of inhibition can phoretic, diuretic, laxative, and anti-diarrheal6,14. be detected. Both the aqueous and alcoholic Additionally, it exhibits antioxidant and anti-in- extracts exhibit a marked activity against Gram flammatory activities via suppression of TNF-a positive and Gram-negative bacterial strains, production, vasodepressant, and even anticancer although some reports7 suggest that the aqueous effect in vitro15-18. Remarkable antipyretic and extract displays more effective than the alcohol- antiulcer activities of C. halicacabum, as well ic one. In detail, among Gram positive species, as an antihyperglycemic effect against strepto- Bacillus subtilis and Bacillus cereus appeared zotocin-induced diabetes, have also been shown to be more susceptible than Staphylococcus au- in experimental animal models19-21. Its aqueous reus to the aqueous leaf extract, whereas among leaf extract increases fertility in male rats and Gram negative bacteria, Escherichia coli was exhibits a significant hepatoprotective effect22. more sensitive to aqueous than the alcoholic The herb has also been shown to have strong pro- extract7. On the other hand, the ethanolic frac- tective activity against diverse infectious diseases tion was found to be more effective than the for its antibacterial, antifungal, and antiparasitic aqueous extract against Gram positive bacterial activity3,23. Although the antimicrobial proper- strains, especially Staphylococcus epidermidis, ties of the plant have extensively been studied, Streptococcus faecalis, Staphylococcus aureus, the precise mechanisms underlying its inhibitory Bacillus subtilis and Bacillus cereus23,25-27. The effect against microbial pathogens have not yet ethanolic extract also displayed remarkable in- been completely clarified. This review summa- hibitory activity against various Gram-nega- rizes available scientific data reported by the tive bacteria, especially Escherichia coli23 and most recent studies describing the antimicrobial Citrobacter freundii26. By contrast, it exerted activity of C. halicacabum. Furthermore, the re- only moderate inhibition of the multidrug resis- view highlights our recent results showing that C. tant Shigella spp., Salmonella typhi, Klebsiella halicacabum exerted an inhibitory effect against pneumoniae, and Enterobacter25 while exerted the dermatophytic fungus Trychophyton rubrum. minimal or no activity against Pseudomonas In addition, by molecular docking simulations, spp.23,25. The last one was found to be more we showed that the fungistatic effect of C. hal- susceptible to benzene followed by acetone, eth- icacabum may be related to the molecular inter- anol, and aqueous extracts23,25-27. A considerable 7136 Antimicrobial properties of C. halicacabum L activity against Streptococcus faecalis, Bacillus Antiparasitic Activity cereus, Bacillus steadher, and some Gram-nega- Among medicinal plants, C. halicacabum holds tive species, including Salmonella typhi, Shigel- promising antiparasitic properties. The leaves la boydii, Klebsiella pneumoniae, and Entero- ethyl acetate extract of the plant was found to bacter, was also obtained with the oil fraction25. have moderate antiplasmodial activity against a Furthermore, the butanol extraction showed a Chloroquine (CQ)-resistant strain of Plasmodium strong inhibitory effect against Micrococcus lu- falciparum, whereas the dichloromethane