Combination Therapy for Bacterial Pathogens: Naturally Derived Antimicrobial Drugs Combined with Ulva lactuca Extract

Article ID: e230821195790 Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: With the growing incidence of microbial pathogenesis, several alternative strategies have been developed. The number of treatments using naturally (e.g., plants, algae, fungi, bacteria, and animals) derived compounds has increased. Importantly, marine-derived products have become a promising and effective approach to combat the antibiotic resistance properties developed by bacterial pathogens. Furthermore, augmenting the sub-inhibitory concentration of the naturally-derived antimicrobial compounds (e.g., hydroxycinnamic acids, terpenes, marine-derived polysaccharides, phenolic compounds) into the naturally derived extracts as a combination therapy to treat the bacterial infection has not been well studied.

Objective: The present study was aimed to prepare green algae Ulva lactuca extract and evaluate its antibacterial activity towards Gram-positive and Gram-negative human pathogenic bacteria. Also, revitalize the antibacterial efficiency of the naturally-derived antimicrobial drugs and conventional antibiotics by mixing their sub-MIC to the U. lactuca extracts.

Methods: Extraction was done using a different organic solvent, and its antibacterial activity was tested towards Gram-positive and Gram-negative pathogens. The minimum inhibitory concentration (MIC) of U. lactuca extracts has been determined towards pathogenic bacteria using the micro broth dilution method. The viable cell counting method was used to determine the minimum bactericidal concentration (MBC). The fractional inhibitory concentration (FIC) assay was utilized to examine the combinatorial impact of sub-MIC of two antibacterial drugs using the micro broth dilution method. The chemical components of the extract were analyzed by GC-MS analysis.

Results: Among all the extracts, n-hexane extract was found to show effective antibacterial activity towards tested pathogens with the lowest MIC and MBC value. Furthermore, the n-hexane extracts have also been used to enhance the efficacy of the naturally-derived (derived from plants and marine organisms) compounds and conventional antibiotics at their sub-inhibitory concentrations. Most of the tested antibiotics and natural drugs at their sub-MIC were found to exhibit synergistic and additive antibacterial activity towards the tested bacterial pathogens.

Conclusions: The combining of U. lactuca n-hexane extracts with natural drugs resulted in synergistic and additive bactericidal effects on Gram-positive and Gram-negative human pathogenic bacteria. The present study shows a new alternative strategy to revitalize the antimicrobial activity of naturally derived compounds for treating human bacterial pathogens.

Keywords: Antibacterial, green algae, extracts, natural drugs, pathogenic bacteria, synergy, Ulva lactuca.

Graphical Abstract

[1]
Levy SB. Antibiotic and antiseptic resistance: impact on public health. Pediatr Infect Dis J 2000; 19(10)(Suppl.): S120-2.
[http://dx.doi.org/10.1097/00006454-200010001-00008] [PMID: 11052402]
[2]
Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18(3): 268-81.
[http://dx.doi.org/10.1111/j.1469-0691.2011.03570.x] [PMID: 21793988]
[3]
Khan F, Pham DTN, Kim Y-M. Alternative strategies for the application of aminoglycoside antibiotics against the biofilm-forming human pathogenic bacteria. Appl Microbiol Biotechnol 2020; 104(5): 1955-76.
[http://dx.doi.org/10.1007/s00253-020-10360-1] [PMID: 31970432]
[4]
Oloketuyi SF, Khan F. Strategies for biofilm inhibition and virulence attenuation of foodborne pathogen-Escherichia coli O157:H7. Curr Microbiol 2017; 74(12): 1477-89.
[http://dx.doi.org/10.1007/s00284-017-1314-y] [PMID: 28744570]
[5]
Chesman MJ, Ilanko A, Blonk B, Cock IE. Developing new antimicrobial therapies: Are synergistic combinations of plant extracts/compounds with conventional antibiotics the solution? Pharmacogn Rev 2017; 11(22): 57-72.
[http://dx.doi.org/10.4103/phrev.phrev_21_17]
[6]
Srinivasan D, Nathan S, Suresh T, Lakshmana Perumalsamy P. Antimicrobial activity of certain Indian medicinal plants used in folkloric medicine. J Ethnopharmacol 2001; 74(3): 217-20.
[http://dx.doi.org/10.1016/S0378-8741(00)00345-7] [PMID: 11274820]
[7]
Mulat M, Pandita A, Khan F. Medicinal plant compounds for combating the multi-drug resistant pathogenic bacteria: A review. Curr Pharm Biotechnol 2019; 20(3): 183-96.
[http://dx.doi.org/10.2174/1872210513666190308133429] [PMID: 30854956]
[8]
Khan F, Oloketuyi SF, Kim YM. Diversity of Bacteria and bacterial products as antibiofilm and antiquorum sensing drugs against pathogenic bacteria. Curr Drug Targets 2019; 20(11): 1156-79.
[http://dx.doi.org/10.2174/1389450120666190423161249] [PMID: 31020938]
[9]
Bamunuarachchi NI, Khan F, Kim YM. Antimicrobial properties of actively purified secondary metabolites isolated from different marine organisms. Curr Pharm Biotechnol 2021; 22(7): 920-44.
[http://dx.doi.org/10.2174/1389201021666200730144536]
[10]
PA (c)rez MJ, FalquA(c) E, DomA-nguez H. Antimicrobial action of compounds from marine seaweed. Mar Drugs 2016; 14(3)E52
[http://dx.doi.org/10.3390/md14030052] [PMID: 27005637]
[11]
Panayidou S, Ioannidou E, Apidianakis Y. Human pathogenic bacteria, fungi, and viruses in Drosophila: disease modeling, lessons, and shortcomings. Virulence 2014; 5(2): 253-69.
[http://dx.doi.org/10.4161/viru.27524] [PMID: 24398387]
[12]
He X, Hwang HM, Aker WG, et al. Synergistic combination of marine oligosaccharides and azithromycin against Pseudomonas aeruginosa. Microbiol Res 2014; 169(9-10): 759-67.
[http://dx.doi.org/10.1016/j.micres.2014.01.001] [PMID: 24529598]
[13]
Ncube B, Finnie JF, Van Staden J. In vitro antimicrobial synergism within plant extract combinations from three South African medicinal bulbs. J Ethnopharmacol 2012; 139(1): 81-9.
[http://dx.doi.org/10.1016/j.jep.2011.10.025] [PMID: 22075455]
[14]
Bassol A. (c) IHN, Juliani HR. Essential oils in combination and their antimicrobial properties. Molecules 2012; 17(4): 3989-4006.
[http://dx.doi.org/10.3390/molecules17043989] [PMID: 22469594]
[15]
Weerakkody NS, Caffin N, Lambert LK, Turner MS, Dykes GA. Synergistic antimicrobial activity of galangal (Alpinia galanga), rosemary (Rosmarinus officinalis) and lemon iron bark (Eucalyptus staigerana) extracts. J Sci Food Agric 2011; 91(3): 461-8.
[http://dx.doi.org/10.1002/jsfa.4206] [PMID: 21218479]
[16]
Wojtyczka RD, Dziedzic A, Idzik D, et al. Susceptibility of Staphylococcus aureus clinical isolates to propolis extract alone or in combination with antimicrobial drugs. Molecules 2013; 18(8): 9623-40.
[http://dx.doi.org/10.3390/molecules18089623] [PMID: 23941882]
[17]
Coppejans E, Leliaert F, Dargent O, Gunasekara R, Clerck O. .Sri Lankan seaweeds: Methodologies and field guide to the dominant species. 2009; 6.
[18]
Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother 2001; 48(Suppl. 1): 5-16.
[http://dx.doi.org/10.1093/jac/48.suppl_1.5] [PMID: 11420333]
[19]
Waitz JA. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobicallyNational committee for clinical laboratory standards 1990.
[20]
Botelho MG. Fractional inhibitory concentration index of combinations of antibacterial agents against cariogenic organisms. J Dent 2000; 28(8): 565-70.
[http://dx.doi.org/10.1016/S0300-5712(00)00039-7] [PMID: 11082524]
[21]
Charway GNA, Park S, Yu D, et al. In vitro antibacterial and synergistic effect of chitosan-phytochemical conjugates against antibiotic resistant fish pathogenic bacteria. Indian J Microbiol 2019; 59(1): 116-20.
[http://dx.doi.org/10.1007/s12088-018-0750-0] [PMID: 30728641]
[22]
Mulugeta M, Fazlurrahman K, Archana P. Chemical composition and antibacterial, anti-biofilm and anti-virulence activities of plant extracts against human pathogenic bacteria. Nat Prod J 2020; 10: 1-15.
[23]
Teichberg M, Fox SE, Olsen YS, et al. Eutrophication and macroalgal blooms in temperate and tropical coastal waters: Nutrient enrichment experiments with Ulva spp. Glob Change Biol 2010; 16(9): 2624-37.
[http://dx.doi.org/10.1111/j.1365-2486.2009.02108.x]
[24]
Felhi S, Daoud A, Hajlaoui H, Mnafgui K, Gharsallah N, Kadri A. Solvent extraction effects on phytochemical constituents profiles, antioxidant and antimicrobial activities and functional group analysis of Ecballium elaterium seeds and peels fruits. J Food Sci Technol 2017; 37: 483-92.
[http://dx.doi.org/10.1590/1678-457x.23516]
[25]
Do QD, Angkawijaya AE, Tran-Nguyen PL, et al. Effect of extraction solvent on total phenol content, total flavonoid content, and antioxidant activity of Limnophila aromatica. J Food Drug Anal 2014; 22(3): 296-302.
[http://dx.doi.org/10.1016/j.jfda.2013.11.001] [PMID: 28911418]
[26]
Fernandes DRP, de Oliveira VP, Yoneshigue Valentin Y. Seaweed biotechnology in Brazil: Six decades of studies on natural products and their antibiotic and other biological activities. J Appl Phycol 2014; 26(5): 1923-37.
[http://dx.doi.org/10.1007/s10811-014-0287-5]
[27]
Ismail A, Ktari L, Ben Redjem Romdhane Y, et al. Antimicrobial fatty acids from green alga Ulva rigida (Chlorophyta). BioMed Res Int 2018; 20183069595
[http://dx.doi.org/10.1155/2018/3069595] [PMID: 30539008]
[28]
Barot M, Ji NN, Kumar R. Bioactive compounds and antifungal activity of three different seaweed species Ulva lactuca, Sargassum tenerrimum and Laurencia obtusa collected from Okha coast, Western India. J Coast Life Med 2016; 4: 284-9.
[http://dx.doi.org/10.12980/jclm.4.2016J5-185]
[29]
Mitra A. Antimicrobial and phytochemical screening of seaweeds: Enteromorpha intestinalis and Ulva lactuca collected from indian sunderbans delta region. IOSR J Pharm Biol Sci 2016; 11: 1-5.
[http://dx.doi.org/10.9790/3008-1104020105]
[30]
Kim B, Kim M-S, Park S-K, et al. Antibacterial effect of Ishige okamurae extract against cutaneous bacterial pathogens and its synergistic antibacterial effect against Pseudomonas aeruginosa. Fish Aquatic Sci 2018; 21(1): 18.
[http://dx.doi.org/10.1186/s41240-018-0096-x]
[31]
Bamunuarachchi NI, Khan F, Kim YM. Bactericidal activity of Sargasssum aquifolium (Turner) C Agardh against gram-positive and gram-negative biofilm-forming pathogenic bacteria. Curr Pham Biotechnol 2021.
[http://dx.doi.org/10.2174/1389201022666210111122230] [PMID: 33430725]
[32]
Kim Y, Kim J-H, Kim D-H, Kim S-H, Kim H-R, Kim Y-M. Synergistic antimicrobial effect of Sargassum serratifolium (C. Agardh) C. Agardh extract against human skin pathogens. Korean J Food Sci Technol 2016; 48: 241-6.
[http://dx.doi.org/10.9721/KJFST.2016.48.3.241]
[33]
Miklasinska-Majdanik M, Kepa M, Wojtyczka RD, Idzik D, Wasik TJ. Phenolic compounds diminish antibiotic resistance of Staphylococcus aureus clinical strains. Int J Environ Res Public Health 2018; 15(10): 2321a.
[http://dx.doi.org/10.3390/ijerph15102321] [PMID: 30360435]
[34]
Anighoro A, Bajorath J, Rastelli G. Polypharmacology: challenges and opportunities in drug discovery. J Med Chem 2014; 57(19): 7874-87.
[http://dx.doi.org/10.1021/jm5006463] [PMID: 24946140]
[35]
Nitsch-Velasquez L. Synergistic effects of natural products and commercial antibiotics. medRxiv 2020; 20186353.
[36]
Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 2009; 16(2-3): 97-110.
[http://dx.doi.org/10.1016/j.phymed.2008.12.018] [PMID: 19211237]
[37]
Borges A, Ferreira C, Saavedra MJ, Simoes M. Antibacterial activity and mode of action of ferulic and gallic acids against pathogenic bacteria. Microb Drug Resist 2013; 19(4): 256-65.
[http://dx.doi.org/10.1089/mdr.2012.0244] [PMID: 23480526]
[38]
Borges A, Saavedra MJ, Simoes M. The activity of ferulic and gallic acids in biofilm prevention and control of pathogenic bacteria. Biofouling 2012; 28(7): 755-67.
[http://dx.doi.org/10.1080/08927014.2012.706751] [PMID: 22823343]
[39]
LuA-s A, Silva F, Sousa S, Duarte AP, Domingues F. Antistaphylococcal and biofilm inhibitory activities of gallic, caffeic, and chlorogenic acids. Biofouling 2014; 30(1): 69-79.
[http://dx.doi.org/10.1080/08927014.2013.845878] [PMID: 24228999]
[40]
Taofiq O, Gonzalez-Paramas AM, Barreiro MF, Ferreira IC. Hydroxycinnamic acids and their derivatives: Cosmeceutical significance, challenges and future perspectives, A Review. Molecules 2017; 22(2)E281
[http://dx.doi.org/10.3390/molecules22020281] [PMID: 28208818]
[41]
Lee DS, Woo JY, Ahn CB, Je JY. Chitosan-hydroxycinnamic acid conjugates: preparation, antioxidant and antimicrobial activity. Food Chem 2014; 148: 97-104.
[http://dx.doi.org/10.1016/j.foodchem.2013.10.019] [PMID: 24262532]
[42]
Kim JH, Yu D, Eom SH, et al. Synergistic antibacterial effects of chitosan-caffeic acid conjugate against antibiotic-resistant acne-related bacteria. Mar Drugs 2017; 15(6)E167
[http://dx.doi.org/10.3390/md15060167] [PMID: 28594356]
[43]
Pei K, Ou J, Huang J, Ou S. p-Coumaric acid and its conjugates: dietary sources, pharmacokinetic properties and biological activities. J Sci Food Agric 2016; 96(9): 2952-62.
[http://dx.doi.org/10.1002/jsfa.7578] [PMID: 26692250]
[44]
Chai B, Jiang W, Hu M, Wu Y, Si H. In vitro synergistic interactions of Protocatechuic acid and Chlorogenic acid in combination with antibiotics against animal pathogens. Synergy 2019; 9100055
[http://dx.doi.org/10.1016/j.synres.2019.100055]
[45]
Hemaiswarya S, Doble M. Synergistic interaction of phenylpropanoids with antibiotics against bacteria. J Med Microbiol 2010; 59(Pt 12): 1469-76.
[http://dx.doi.org/10.1099/jmm.0.022426-0] [PMID: 20724513]
[46]
Liu X, Cai J, Chen H, et al. Antibacterial activity and mechanism of linalool against Pseudomonas aeruginosa. Microb Pathog 2020; 141103980
[http://dx.doi.org/10.1016/j.micpath.2020.103980] [PMID: 31962183]
[47]
Onawunmi GO. Evaluation of the antimicrobial activity of citral. Lett Appl Microbiol 1989; 9(3): 105-8.
[http://dx.doi.org/10.1111/j.1472-765X.1989.tb00301.x]
[48]
Jayaraman P, Sakharkar MK, Lim CS, Tang TH, Sakharkar KR. Activity and interactions of antibiotic and phytochemical combinations against Pseudomonas aeruginosa in vitro. Int J Biol Sci 2010; 6(6): 556-68.
[http://dx.doi.org/10.7150/ijbs.6.556] [PMID: 20941374]
[49]
Bhattamisra SK, Kuean CH, Chieh LB, et al. Antibacterial activity of geraniol in combination with standard antibiotics against Staphylococcus aureus, Escherichia coli and Helicobacter pylori. Nat Prod Commun 2018; 13(7)
[http://dx.doi.org/10.1177/1934578X1801300701]
[50]
Langeveld WT, Veldhuizen EJA, Burt SA. Synergy between essential oil components and antibiotics: A review. Crit Rev Microbiol 2014; 40(1): 76-94.
[http://dx.doi.org/10.3109/1040841X.2013.763219] [PMID: 23445470]
[51]
Gupta P, Patel DK, Gupta VK, Pal A, Tandon S, Darokar MP. Citral, a monoterpenoid aldehyde interacts synergistically with norfloxacin against methicillin resistant Staphylococcus aureus. Phytomedicine 2017; 34: 85-96.
[http://dx.doi.org/10.1016/j.phymed.2017.08.016] [PMID: 28899514]
[52]
Herman A, Tambor K, Herman A. Linalool affects the antimicrobial efficacy of essential oils. Curr Microbiol 2016; 72(2): 165-72.
[http://dx.doi.org/10.1007/s00284-015-0933-4] [PMID: 26553262]
[53]
Aelenei P, Rimbu CM, Guguianu E, et al. Coriander essential oil and linalool - interactions with antibiotics against Gram-positive and Gram-negative bacteria. Lett Appl Microbiol 2019; 68(2): 156-64.
[http://dx.doi.org/10.1111/lam.13100] [PMID: 30471142]
[54]
Khan F, Pham DTN, Oloketuyi SF, Manivasagan P, Oh J, Kim YM. Chitosan and their derivatives: Antibiofilm drugs against pathogenic bacteria. Colloids Surf B Biointerfaces 2020; 185110627
[http://dx.doi.org/10.1016/j.colsurfb.2019.110627] [PMID: 31732391]
[55]
Poveda-Castillo GDC, Rodrigo D. MartA-nez A, Pina-PA(c)rez MC. Bioactivity of fucoidan as an antimicrobial agent in a new functional beverage. Beverages 2018; 4(3): 64.
[http://dx.doi.org/10.3390/beverages4030064]
[56]
Lee KY, Jeong MR, Choi SM, Na SS, Cha JD. Synergistic effect of fucoidan with antibiotics against oral pathogenic bacteria. Arch Oral Biol 2013; 58(5): 482-92.
[http://dx.doi.org/10.1016/j.archoralbio.2012.11.002] [PMID: 23399045]
[57]
Wang FF, Yao Z, Wu HG, Zhang SX, Zhu NN, Gai X. Antibacterial activities of kappa-carrageenan oligosaccharides. Appl Mech Mater 2012; 108: 194-9.
[http://dx.doi.org/10.4028/www.scientific.net/AMM.108.194]
[58]
Briones AV, Sato T, Bigol UG. Antibacterial activity of polyethylenimine/carrageenan multilayer against pathogenic bacteria. Adv Chem Eng Sci 2014; 4: 9.
[http://dx.doi.org/10.4236/aces.2014.42026]
[59]
Maciag-Dorszynska M, Wegrzyn G, Guzow-Krzeminska B. Antibacterial activity of lichen secondary metabolite usnic acid is primarily caused by inhibition of RNA and DNA synthesis. FEMS Microbiol Lett 2014; 353(1): 57-62.
[http://dx.doi.org/10.1111/1574-6968.12409] [PMID: 24571086]
[60]
Gupta VK, Verma S, Gupta S, et al. Membrane-damaging potential of natural L-(-)-usnic acid in Staphylococcus aureus. Eur J Clin Microbiol Infect Dis 2012; 31(12): 3375-83.
[http://dx.doi.org/10.1007/s10096-012-1706-7] [PMID: 22865029]
[61]
Lou Z, Wang H, Rao S, Sun J, Ma C, Li J. p-Coumaric acid kills bacteria through dual damage mechanisms. Food Control 2012; 25(2): 550-4.
[http://dx.doi.org/10.1016/j.foodcont.2011.11.022]
[62]
Mitani T, Ota K, Inaba N, Kishida K, Koyama HA. Antimicrobial activity of the phenolic compounds of prunus mume against enterobacteria. Biol Pharm Bull 2018; 41(2): 208-12.
[http://dx.doi.org/10.1248/bpb.b17-00711] [PMID: 29386480]
[63]
Boz H. p-Coumaric acid in cereals: Presence, antioxidant and antimicrobial effects. Int J Food Sci Technol 2015; 50(11): 2323-8.
[http://dx.doi.org/10.1111/ijfs.12898]
[64]
Engels C, Schieber A. GAnzle MG. Sinapic acid derivatives in defatted Oriental mustard (Brassica juncea L.) seed meal extracts using UHPLC-DAD-ESI-MSnand identification of compounds with antibacterial activity. Eur Food Res Technol 2012; 234(3): 535-42.
[http://dx.doi.org/10.1007/s00217-012-1669-z]
[65]
Chen C. Sinapic acid and its derivatives as medicine in oxidative stress-induced diseases and aging. Oxid Med Cell Longev 2016; 20163571614
[http://dx.doi.org/10.1155/2016/3571614] [PMID: 27069529]
[66]
Nowak H, Kujawa K, Zadernowski R, Roczniak B. KozLowska H. Antioxidative and bactericidal properties of phenolic compounds in rapeseeds. Lipid-Fett 1992; 94(4): 149-52.
[http://dx.doi.org/10.1002/lipi.19920940406]
[67]
Lima VN, Oliveira-Tintino CDM, Santos ES, et al. Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol. Microb Pathog 2016; 99: 56-61.
[http://dx.doi.org/10.1016/j.micpath.2016.08.004] [PMID: 27497894]
[68]
Khan F, Bamunuarachchi NI, Tabassum N, Kim YM. Caffeic acid and its derivatives: Antimicrobial drugs towards microbial pathogens. J Agric Food Chem 2021; 69(10): 2979-3004.
[http://dx.doi.org/10.1021/acs.jafc.0c07579] [PMID: 33656341]
[69]
Zhu M, Ge L, Lyu Y, et al. Preparation, characterization and antibacterial activity of oxidized κ-carrageenan. Carbohydr Polym 2017; 174: 1051-8.
[http://dx.doi.org/10.1016/j.carbpol.2017.07.029] [PMID: 28821027]
[70]
Pattnaik S, Subramanyam VR, Bapaji M, Kole CR. Antibacterial and antifungal activity of aromatic constituents of essential oils. Microbios 1997; 89(358): 39-46.
[PMID: 9218354]
[71]
Lira MHPd, Andrade JA§nior FPd, Moraes GFQ, Macena GS, Pereira FO, Lima IO. Antimicrobial activity of geraniol: An integrative review. J Essent Oil Res 2020; 32(3): 187-97.
[http://dx.doi.org/10.1080/10412905.2020.1745697]
[72]
Kim J, Marshall MR, Wei C-i. Antibacterial activity of some essential oil components against five foodborne pathogens. J Agric Food Chem 1995; 43(11): 2839-45.
[http://dx.doi.org/10.1021/jf00059a013]
[73]
Holland K, Bojar R. Antimicrobial effects of azelaic acid. J Dermatol Treat 1993; 4(sup1): S8-S11.
[http://dx.doi.org/10.3109/09546639309082152]
[74]
Bridi H, Meirelles GC, von Poser GL. Structural diversity and biological activities of phloroglucinol derivatives from Hypericum species. Phytochemistry 2018; 155: 203-32.
[http://dx.doi.org/10.1016/j.phytochem.2018.08.002] [PMID: 30153613]
[75]
Lee HB, Kim JC, Lee SM. Antibacterial activity of two phloroglucinols, flavaspidic acids AB and PB, from Dryopteris crassirhizoma. Arch Pharm Res 2009; 32(5): 655-9.
[http://dx.doi.org/10.1007/s12272-009-1502-9] [PMID: 19471878]
[76]
Norizan SNM, Yin W-F, Chan K-G. Caffeine as a potential quorum sensing inhibitor. Sensors (Basel) 2013; 13(4): 5117-29.
[http://dx.doi.org/10.3390/s130405117] [PMID: 23598500]
[77]
Francolini I, Norris P, Piozzi A, Donelli G, Stoodley P. Usnic acid, a natural antimicrobial agent able to inhibit bacterial biofilm formation on polymer surfaces. Antimicrob Agents Chemother 2004; 48(11): 4360-5.
[http://dx.doi.org/10.1128/AAC.48.11.4360-4365.2004] [PMID: 15504865]
[78]
Victor K, Boris L, Athina G, et al. Design, synthesis and antimicrobial activity of usnic acid derivatives. MedChemComm 2018; 9(5): 870-82.
[http://dx.doi.org/10.1039/C8MD00076J] [PMID: 30108976]