Humus acids are promising compounds for the creation of new antimicrobial drugs

Abstract

Infectious diseases are still the leading causes of morbidity and mortality worldwide, which prompts the need to prioritize research and development of new antimicrobial drugs with high pharmacological activity and favorable safety profile. One of the key directions in this field is the study of the potential of natural compounds, such as humus acids. Recent studies have shown that humus acids can exhibit multidirectional activity against various microorganisms and demonstrate synergistic pharmacological interaction with other drugs.

This review aimed to present a generalized and systematic analysis of currently available information on the known pharmacological effects and possible mechanisms of the antibacterial, antiviral, and antifungal activities of humus acids.

Keywords

humus acids / antibacterial properties of humus acids / antiviral properties of humus acids / antifungal properties of humus acids / humic acid / fulvic acid

References

[1] World Health Organization. World health statistics 2021: monitoring health for the SDGs, sustainable development goals [Internet]. Available from: https://apps.who.int/iris/handle/10665/342703

[2] World Health Organization. World health statistics 2021: monitoring health for the SDGs, sustainable development goals [Internet]. Доступ по ссылке: https://apps.who.int/iris/handle/10665/342703

[3] Institute for Health Metrics and Evaluation. Findings from the Global Burden of Disease Study 2017 [Internet]. Available from: https://www.healthdata.org/policy-report/findings-global-burden-disease-study-2017

[4] Institute for Health Metrics and Evaluation. Findings from the Global Burden of Disease Study 2017. [Internet]. Доступ по ссылке: https://www.healthdata.org/policy-report/findings-global-burden-disease-study-2017

[5] Baker RE, Mahmud AS, Miller IF, et al. Infectious disease in an era of global change. Nat Rev Microbiol. 2022;20(4):193–205. doi: 10.1038/s41579-021-00639-z

[6] Baker R.E., Mahmud A.S., Miller I.F., et al. Infectious disease in an era of global change // Nat Rev Microbiol. 2022. Vol. 20, N 4. P. 193–205. doi: 10.1038/s41579-021-00639-z

[7] Tong S, Ebi K, Olsen J. Infectious disease, the climate, and the future. Environ Epidemiol. 2021;5(2):133. doi: 10.1097/EE9.0000000000000133

[8] Tong S., Ebi K., Olsen J. Infectious disease, the climate, and the future // Environ Epidemiol. 2021. Vol. 5, N 2. P. 133. doi: 10.1097/EE9.0000000000000133

[9] Polgreen PM, Polgreen EL. Infectious diseases, weather, and climate. Clin Infect Dis. 2018;66(6):815–817. doi: 10.1093/cid/cix1105

[10] Polgreen P.M., Polgreen E.L. Infectious diseases, weather, and climate // Clin Infect Dis. 2018. Vol. 66, N 6. P. 815–817. doi: 10.1093/cid/cix1105

[11] Craven M, Sabow A, Van der Veken L, et al., editors. Not the last pandemic: Investing now to reimagine public-health systems [Internet]. New York: McKinsey Report; 2021. [cited 2023 Apr 1]. Available from: https://www.mckinsey.com/industries/public-and-social-sector/our-insights/not-the-last-pandemic-investing-now-to-reimagine-public-health-systems#/

[12] Craven M., Sabow A., Van der Veken L., et al., editors. Not the last pandemic: Investing now to reimagine public-health systems [Internet]. New York : McKinsey Report, 2020. Дата обращения: 01.04.2023. Доступ по ссылке: https://www.mckinsey.com/industries/public-and-social-sector/our-insights/not-the-last-pandemic-investing-now-to-reimagine-public-health-systems#/

[13] Orlov DS. Humic substances in the biosphere. Soros Educational Journal. 1997;(2):56–63. (In Russ).

[14] Орлов Д.С. Гуминовые вещества в биосфере // Соросовский образовательный журнал. 1997. № 2. С. 56–63.

[15] Perminova IV. Analiz, klassifikaciya i prognoz svojstv gumusovyh kislot [dissertation]. Moscow; 2000. Available from: http://mgumus.chem.msu.ru/publication/01-titul.pdf (In Russ).

[16] Перминова И.В. Анализ, классификация и прогноз свойств гумусовых кислот : дис. … докт. хим. наук. Москва, 2000. Режим доступа: http://mgumus.chem.msu.ru/publication/01-titul.pdf Дата обращения: 01.04.2023.

[17] Avvakumova NP. Sostav i biologicheskie svojstva gumusovyh kislot peloidov: fundamental’nye i prikladnye aspekty [dissertation]. Moscow; 2000. Available from: http://dlib.rsl.ru/rsl01002000000/rsl01002606000/rsl01002606904/rsl01002606904.pdf (In Russ).

[18] Аввакумова Н.П. Состав и биологические свойства гумусовых кислот пелоидов: фундаментальные и прикладные аспекты : дис. … докт. биол. наук. Самара, 2003. Режим доступа: http://dlib.rsl.ru/rsl01002000000/rsl01002606000/rsl01002606904/rsl01002606904.pdf Дата обращения: 01.04.2023.

[19] Danchenko NN. Funkcional’nyj sostav gumusovyh kislot: opredelenie i vzaimosvyaz’ s reakcionnoj sposobnost’yu [dissertation]. Moscow; 1997. Available from: http://www.mgumus.chem.msu.ru/researches/Avtoreferaty/danchenko-diss.pdf (In Russ).

[20] Данченко Н.Н. Функциональный состав гумусовых кислот: определение и взаимосвязь с реакционной способностью : дис. канд. хим. наук. Москва, 1997. Режим доступа: http://www.mgumus.chem.msu.ru/researches/Avtoreferaty/danchenko-diss.pdf Дата обращения: 01.04.2023.

[21] Aleksandrova LN. Organicheskoe veshhestvo pochvy i processy ee transformacii. Leningrad: Nauka. Leningradskoe otdelenie; 1980. (In Russ).

[22] Александрова Л.Н. Органическое вещество почвы и процессы ее трансформации. Ленинград : Наука. Ленинградское отделение, 1980.

[23] Kononova MM. Problema pochvennogo gumusa i sovremennye zadachi ego izuchenija. Moscow: Izdatel’stvo Akademii nauk SSSR; 1951. (In Russ).

[24] Кононова М.М. Проблема почвенного гумуса и современные задачи его изучения. Москва : Издательство Академии наук СССР, 1951.

[25] Lishtvan II, Kruglickij NN, Tretinnik VJu. Fiziko-himicheskaja mehanika guminovyh veshhestv. Minsk: Nauka i tehnika; 1976. (In Russ).

[26] Лиштван И.И., Круглицкий Н.Н., Третинник В.Ю. Физико-химическая механика гуминовых веществ. Минск : Наука и техника, 1976.

[27] Orlov DS. Gumusovye kisloty pochv i obshhaja teorija gumifikacii. Moscow: Izdatel’stvo MGU; 1990. 325 p. (In Russ).

[28] Орлов Д.С. Гумусовые кислоты почв и общая теория гумификации. Москва : Издательство МГУ, 1990. 325 с.

[29] Zhdanova AV. Izuchenie strukturnyh komponentov i fiziko-himicheskih svojstv guminovyh veshchestv nizkomineralizovannyh ilovyh sul’fidnyh gryazej kak istochnika antioksidantnyh lekarstvennyh sredstv [dissertation]. Samara; 2011. Available from: http://dlib.rsl.ru/rsl01004000000/rsl01004846000/rsl01004846945/rsl01004846945.pdf (In Russ).

[30] Жданова А.В. Изучение структурных компонентов и физико-химических свойств гуминовых веществ низкоминерализованных иловых сульфидных грязей как источника антиоксидантных лекарственных средств : дис. … канд. фарм. наук. Самара, 2011. Режим доступа: http://dlib.rsl.ru/rsl01004000000/rsl01004846000/rsl01004846945/rsl01004846945.pdf Дата обращения: 01.04.2023.

[31] Avvakumova NP, Glubokova MN, Zhdanova AV, et al. Optimization of humic acids dialysis. Izvestia of Samara Scientific Center of the Russian Academy of Sciences. 2009;11(1): 1256–1258. (In Russ).

[32] Аввакумова Н.П., Глубокова М.Н., Жданова А.В., и др. Оптимизация диализа гуминовых кислот // Известия Самарского научного центра Российской академии наук. 2009. Т. 11, № 1. С. 1256–1258.

[33] Tadigieva NZ, Coj EG, Turovskaja SI. Antibakterial’naja aktivnost’ guminovogo preparata iz lechebnoj torfjanoj grjazi Dzhelal. Biologicheskie nauki. 1991;(10):109–113. (In Russ).

[34] Тадигиева Н.З., Цой Е.Г., Туровская С.И. Антибактериальная активность гуминового препарата из лечебной торфяной грязи Джелал // Биологические науки. 1991. № 10. С. 109–113.

[35] Krasnikova ES, Pavlenko VV, Martynov IS. The study of bactericidal and fungicidal activity of feed additives based on humic acids. Uchenye zapiski Kazanskoj gosudarstvennoj akademii veterinarnoj mediciny im. N.Je. Baumana. 2019;239(3):158–160. (In Russ). doi: 10.31588/2413-4201-1883-239-3-158-160

[36] Красникова Е.С., Павленко В.В., Матренов И.С. Изучение бактерицидной и фунгицидной активности кормовой добавки на основе гуминовых кислот // Ученые записки Казанской государственной академии ветеринарной медицины им. Н.Э. Баумана. 2019. Т. 239, №. 3. С. 158–160. doi: 10.31588/2413-4201-1883-239-3-158-160

[37] Verrillo M, Salzano M, Savy D, et al. Antibacterial and antioxidant properties of humic substances from composted agricultural biomasses. Chem Biol Technol Agric. 2022;9:28. doi: 10.1186/s40538-022-00291-6

[38] Verrillo M., Salzano M., Savy D., et al. Antibacterial and antioxidant properties of humic substances from composted agricultural biomasses // Chem Biol Technol Agric. 2022. Vol. 9. P. 28. doi: 10.1186/s40538-022-00291-6

[39] Hassett DJ, Bisesi MS, Hartenstein R. Bactericidal action of humic acids. Soil Biology and Biochemistry. 1987;19(1):111–113. doi: 10.1016/0038-0717(87)90134-9

[40] Hassett D.J., Bisesi M.S., Hartenstein R. Bactericidal action of humic acids // Soil Biology and Biochemistry. 1987. Vol. 19, N 1. P. 111–113. doi: 10.1016/0038-0717(87)90134-9

[41] Khuda F, Anjum M, Khan S, et al. Antimicrobial, anti-inflammatory and antioxidant activities of natural organic matter extracted from cretaceous shales in district Nowshera-Pakistan. Arabian Journal of Chemistry. 2022;15(2):103633.

[42] Khuda F., Anjum M., Khan S., et al. Antimicrobial, anti-inflammatory and antioxidant activities of natural organic matter extracted from cretaceous shales in district Nowshera-Pakistan // Arabian Journal of Chemistry. 2022. Vol. 15, N 2. P. 103633.

[43] Litvin VA, Njoh RA. Quercetin as a precursor in the synthesis of analogues of fulvicacids and their antibacterial properties. Voprosy khimii i khimicheskoi tekhnologii. 2021;(2):56–64. doi: 10.32434/0321-4095-2021-135-2-56-64

[44] Litvin V.A., Njoh R.A. Quercetin as a precursor in the synthesis of analogues of fulvicacids and their antibacterial properties // Voprosy khimii i khimicheskoi tekhnologii. 2021. N 2. P. 56–64. doi: 10.32434/0321-4095-2021-135-2-56-64

[45] Van Rensburg CE, Van Straten A, Dekker J. An in vitro investigation of the antimicrobial activity of oxifulvic acid. J Antimicrob Chemother. 2000;46(5):853. doi: 10.1093/jac/46.5.853

[46] Van Rensburg C.E., Van Straten A., Dekker J. An in vitro investigation of the antimicrobial activity of oxifulvic acid // J Antimicrob Chemother. 2000. Vol. 46, N. 5. P. 853. doi: 10.1093/jac/46.5.853

[47] Ansorg R, Rochus W. Studies on the antimicrobial effect of natural and synthetic humic acids (author’s transl). Arzneimittelforschung. 1978;28(12):2195–2198.

[48] Ansorg R., Rochus W. Studies on the antimicrobial effect of natural and synthetic humic acids (author’s transl) // Arzneimittelforschung. 1978. Vol. 28, N 12. P. 2195–2198.

[49] Gorovaja AI, Orlov DS, Shherbenko OV. Guminovye veshhestva. Kiev: Naukova dumka; 1995. (In Russ).

[50] Горовая А.И., Орлов Д.С., Щербенко О.В. Гуминовые вещества. Киев : Наукова думка, 1995.

[51] Popov AI, Zelenkov VN, Teplyakova TV. Biological activity and biochemistry of humic substances. Part 2. Medical and biological aspect. (Literature review). Bulletin of the Russian Academy of Natural Sciences. 2016;(5):9–16. (In Russ).

[52] Попов А.И., Зеленков В.Н., Теплякова Т.В. Биологическая активность и биохимия гуминовых веществ. Часть 2. Медико-биологический аспект (обзор литературы) // Вестник Российской Академии естественных наук. 2016. № 5. С. 9–16.

[53] Man D, Pisarek I, Braczkowski M, et al. The impact of humic and fulvic acids on the dynamic properties of liposome membranes: the ESR method. J Liposome Res. 2014;24(2):106–112. doi: 10.3109/08982104.2013.839998

[54] Man D., Pisarek I., Braczkowski M., et al. The impact of humic and fulvic acids on the dynamic properties of liposome membranes: the ESR method // J Liposome Res. 2014. Vol. 24, N 2. P. 106–112. doi: 10.3109/08982104.2013.839998

[55] de Wit H. Proton and metal ion binding to humic substances. Wageningen: Wageningen University and Research; 1992.

[56] de Wit H. Proton and metal ion binding to humic substances. Wageningen : Wageningen University and Research, 1992.

[57] de Melo BA, Motta FL, Santana MH. Humic acids: Structural properties and multiple functionalities for novel technological developments. Mater Sci Eng C Mater Biol Appl. 2016;(62):967–974. doi: 10.1016/j.msec.2015.12.001

[58] de Melo B.A., Motta F.L., Santana M.H. Humic acids: structural properties and multiple functionalities for novel technological developments // Mater Sci Eng C Mater Biol Appl. 2016. Vol. 62. P. 967–974. doi: 10.1016/j.msec.2015.12.001

[59] Mikhnevich TA, Vyatkina AV, Grigorenko VG, et al. Inhibition of class A β-lactamase (TEM-1) by narrow fractions of humic substances. ACS omega. 2021;6(37):23873–23883. doi: 10.1021/acsomega.1c02841

[60] Mikhnevich T.A., Vyatkina A.V., Grigorenko V.G., et al. Inhibition of class A β-lactamase (TEM-1) by narrow fractions of humic substances // ACS omega. 2021. Vol. 6, N 37. P. 23873–23883. doi: 10.1021/acsomega.1c02841

[61] Kravtsova D, Cherkasova T, Rubtsova M, et al. Humic substances potentiate inhibitory activity of sulbactam with respect to β-lactamase TEM-1. In: Perminova I, editors. Fifth International Conference of CIS IHSS on Humic Innovative Technologies «Humic substances and living systems» (HIT-2019); 2019 October 19–23; Moscow, Russia. Moscow: Desktop publishing by Alexander Polyakov; 2019. p. 105.

[62] Kravtsova D., Cherkasova T., Rubtsova M., et al. Humic substances potentiate inhibitory activity of sulbactam with respect to β-lactamase TEM-1. In: Perminova I., editor. Fifth International Conference of CIS IHSS on Humic Innovative Technologies «Humic substances and living systems» (HIT-2019); 2019 October 19–23; Moscow, Russia. Moscow : Desktop publishing by Alexander Polyakov; 2019. p. 105.

[63] Klöcking R, Sprössig M. Antiviral properties of humic acids. Experientia. 1972;28(5):607–608. doi: 10.1007/BF01931906

[64] Klöcking R., Sprössig M. Antiviral properties of humic acids // Experientia. 1972. Vol. 28, N 5. P. 607–608. doi: 10.1007/BF01931906

[65] Klöcking R, Helbig B. Medical aspects and applications of humic substances. In: Steinbüchel A, Marchessault RH, editors. Biopolymers for Medical and Pharmaceutical Applications. Weinheim: WILEY-VCH Verlag GmbH & C. KGaA; 2005. p. 3–16.

[66] Klöcking R., Helbig B. Medical aspects and applications of humic substances. In: Steinbüchel A., Marchessault R.H., editors. Biopolymers for Medical and Pharmaceutical Applications. Weinheim : WILEY-VCH Verlag GmbH & C. KGaA, 2005. p. 3–16.

[67] Socol DC. Clinical review of humic acid as an antiviral: Leadup to translational applications in clinical humeomics. Front Pharmacol. 2022;(13):1–11. doi: 10.3389/fphar.2022.1018904

[68] Socol D.C. Clinical review of humic acid as an antiviral: leadup to translational applications in clinical humeomics // Front Pharmacol. 2022. Vol. 13. P. 1–11. doi: 10.3389/fphar.2022.1018904

[69] Hajdrik P, Pályi B, Kis Z, et al. In vitro determination of inhibitory effects of humic substances complexing Zn and Se on SARS-CoV-2 virus replication. Foods. 2022;11(5):694. doi: 10.3390/foods11050694

[70] Hajdrik P., Pályi B., Kis Z., et al. In vitro determination of inhibitory effects of humic substances complexing Zn and Se on SARS-CoV-2 virus replication // Foods. 2022. Vol. 11, N. 5. P. 694. doi: 10.3390/foods11050694

[71] Nosik DN, Nosik NN, Teplyakova TV, et al. Antiviral activity of extracts of basidiomycetes and humic compounds against human immunodeficiency virus (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus 1) and Herpes simplex virus (Herpesviridae: Simplexvirus: Human alphaherpesvirus 1). Problems of Virology. 2020;65(5):276–283. (In Russ). doi: 10.36233/0507-4088-2020-65-5-4

[72] Носик Д.Н., Носик Н.Н., Теплякова Т.В., и др. Противовирусная активность экстрактов базидиомицетов и гуминовых соединений в отношении вируса иммунодефицита человека (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus 1) и вируса простого герпеса (Herpesviridae: Simplexvirus: Human alphaherpesvirus 1) // Вопросы вирусологии. 2020. Т. 65, № 5. С. 276–283. doi: 10.36233/0507-4088-2020-65-5-4

[73] Hafez M, Popov AI, Zelenkov VN, et al. Humic substances as an environmental-friendly organic wastes potentially help as natural anti-virus to inhibit COVID-19. Science Archives. 2020;1(2):53–60. doi: 10.47587/SA.2020.1202

[74] Hafez M., Popov A.I., Zelenkov V.N., et al. Humic substances as an environmental-friendly organic wastes potentially help as natural anti-virus to inhibit COVID-19 // Science Archives. 2020. Vol. 1, N 2. P. 53–60. doi: 10.47587/SA.2020.1202

[75] Dekker J, Medlen CE, inventor; Enerkom (Proprietary) Limited, assignee. Fulvic acid and its use in the treatment of various conditions. United States Patent US 006569900B1. 2003 May 27.

[76] Dekker J., Medlen C.E., inventor; Enerkom (Proprietary) Limited, assignee. Fulvic acid and its use in the treatment of various conditions. United States Patent US 006569900B1. 2003 May 27.

[77] Zhernov Y. Natural humic substances interfere with multiple stages of the replication cycle of human immunodeficiency virus. Journal of Allergy and Clinical Immunology. 2018;141(2):233. doi: https://doi.org/10.1016/j.jaci.2017.12.737

[78] Zhernov Y. Natural humic substances interfere with multiple stages of the replication cycle of human immunodeficiency virus // Journal of Allergy and Clinical Immunology. 2018. Vol. 141, N 2. P. 233. doi: https://doi.org/10.1016/j.jaci.2017.12.737

[79] Spiridonov AM, Zhirnov YV, Avvakumova NP, et al. Antiviral activity of fractions of humic substances of peloids against strains of human immunodeficiency virus type 1. Russian Journal of Infection and Immunity. 2012;2(1):424–424. (In Russ).

[80] Спиридонов А.М., Жирнов Ю.В., Аввакумова Н.П., и др. Антивирусная активность фракций гуминовых веществ пелоидов в отношении штаммов вируса иммунодефицита человека 1 типа // Инфекция и иммунитет. 2012. Т. 2, № 1. С. 424–424.

[81] Kornilaeva GV, Siniavin AE, Schultz A, et al. The differential Anti-HIV effect of a new humic substance-derived preparation in diverse cells of the immune system. Acta Naturae. 2019;11(2):68–76. doi: 10.32607/20758251-2019-11-2-68-76

[82] Kornilaeva G.V., Siniavin A.E., Schultz A., et al. The differential Anti-HIV effect of a new humic substance-derived preparation in diverse cells of the immune system // Acta Naturae. 2019. Vol. 11, N 2. P. 68–76. doi: 10.32607/20758251-2019-11-2-68-76

[83] Zhernov YV, Konstantinov AI, Zherebker A, et al. Antiviral activity of natural humic substances and shilajit materials against HIV-1: Relation to structure. Environmental Research. 2021;(193):110312. doi: 10.1016/j.envres.2020.110312

[84] Zhernov Y.V., Konstantinov A.I., Zherebker A., et al. Antiviral activity of natural humic substances and shilajit materials against HIV-1: relation to structure // Environmental Research. 2021. N 193. P. 110312. doi: 10.1016/j.envres.2020.110312

[85] Meerbach A, Neyts J, Balzarini J, et al. In vitro activity of polyhydroxycarboxylates against herpesviruses and HIV. Antivir Chem Chemother. 2001;12(6):337–345. doi: 10.1177/095632020101200603

[86] Meerbach A., Neyts J., Balzarini J., et al. In vitro activity of polyhydroxycarboxylates against herpesviruses and HIV // Antivir Chem Chemother. 2001. Vol. 12, N 6. P. 337–345. doi: 10.1177/095632020101200603

[87] Sherry L, Jose A, Murray C, et al. Carbohydrate derived fulvic acid: an in vitro investigation of a novel membrane active antiseptic agent against Candida albicans biofilms. Front Microbiol. 2012;29(3):116. doi: 10.3389/fmicb.2012.00116

[88] Sherry L., Jose A., Murray C., et al. Carbohydrate derived fulvic acid: an in vitro investigation of a novel membrane active antiseptic agent against Candida albicans biofilms // Front Microbiol. 2012. Vol. 29, N 3. P. 116. doi: 10.3389/fmicb.2012.00116

[89] Saleh AA, Yassin M, El-Naggar K, et al. Effect of dietary supplementation of humic acid and lincomycin on growth performance, nutrient digestibility, blood biochemistry, and gut morphology in broilers under clostridium infection. Journal of Applied Animal Research. 2022;50(1):440–452. doi: 10.1080/09712119.2022.2089674

[90] Saleh A.A., Yassin M., El-Naggar K., et al. Effect of dietary supplementation of humic acid and lincomycin on growth performance, nutrient digestibility, blood biochemistry, and gut morphology in broilers under clostridium infection // Journal of Applied Animal Research. 2022. Vol. 50, N 1. P. 440–452. doi: 10.1080/09712119.2022.2089674

[91] Helbig B, Klöcking R, Wutzler P. Anti-herpes simplex virus type 1 activity of humic acid-like polymers and their o-diphenolic starting compounds. Antivir Chem Chemother. 1997;8(3):265–273.

[92] Helbig B., Klöcking R., Wutzler P. Anti-herpes simplex virus type 1 activity of humic acid-like polymers and their o-diphenolic starting compounds // Antivir Chem Chemother. 1997. Vol. 8, N 3. P. 265–273.

[93] Gu C, Karthikeyan KG, Sibley SD, Pedersen JA. Complexation of the antibiotic tetracycline with humic acid. Chemosphere. 2007;66(8):1494–1501. doi: 10.1016/j.chemosphere.2006.08.028

[94] Gu C., Karthikeyan K.G., Sibley S.D., Pedersen JA. Complexation of the antibiotic tetracycline with humic acid // Chemosphere. 2007. Vol. 66, N 8. P. 1494–1501. doi: 10.1016/j.chemosphere.2006.08.028

[95] Warn P, Leivers SW, inventor; Natracine UK Limited, assignee. Fulvic acid in combination with fluconazole or amphotericin b for the treatment of fungal infections. United States patent US 20120035125A1. 2012 Feb 9.

[96] Warn P., Leivers S.W., inventor; Natracine UK Limited, assignee. Fulvic acid in combination with fluconazole or amphotericin b for the treatment of fungal infections. United States patent US 20120035125A1. 2012 Feb 9.

[97] Leivers SW, Warn P, inventor; Natracine UK Limited, assignee. Fulvic acid and antibiotic combination for the inhibition or treatment of multi-drug resistant bacteria. United States patent US 9265744B2. 2016 Feb 23.

[98] Leivers S.W., Warn P., inventor; Natracine UK Limited, assignee. Fulvic acid and antibiotic combination for the inhibition or treatment of multi-drug resistant bacteria. United States patent US 9265744B2. 2016 Feb 23.

[99] Fernandes AC, Medlen CE, Leivers S, inventor; Pfeinsmith Ltd., assignee. Fulvic acid and antibiotic combination. United States patent US 8445452B2. 2013 May 21.

[100] Fernandes A.C., Medlen C.E., Leivers S., inventor; Pfeinsmith Ltd., assignee. Fulvic acid and antibiotic combination. United States patent US 8445452B2. 2013 May 21.

RIGHTS & PERMISSIONS

Eco-Vector