Potential cannabidiol (CBD) repurposing as antibacterial and promising therapy of CBD plus polymyxin B (PB) against PB-resistant gram-negative bacilli.


Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
19 04 2022
Historique:
received: 27 10 2021
accepted: 04 03 2022
entrez: 20 4 2022
pubmed: 21 4 2022
medline: 22 4 2022
Statut: epublish

Résumé

This study aimed to assess the ultrapure cannabidiol (CBD) antibacterial activity and to investigate the antibacterial activity of the combination CBD + polymyxin B (PB) against Gram-negative (GN) bacteria, including PB-resistant Gram-negative bacilli (GNB). We used the standard broth microdilution method, checkerboard assay, and time-kill assay. CBD exhibited antibacterial activity against Gram-positive bacteria, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis), and Mycobacterium tuberculosis, but not against GNB. For most of the GNB studied, our results showed that low concentrations of PB (≤ 2 µg/mL) allow CBD (≤ 4 µg/mL) to exert antibacterial activity against GNB (e.g., Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii), including PB-resistant GNB. CBD + PB also showed additive and/or synergistic effect against LOS-expressing GND. Time-kill assays results showed that the combination CBD + PB leads to a greater reduction in the number of colony forming units per milliliter compared to CBD and PB alone, at the same concentration used in combination, and the combination CBD + PB was synergistic for all four PB-resistant K. pneumoniae isolates evaluated. Our results show that CBD has translational potential and should be further explored as a repurposed antibacterial agent in clinical trials. The antibacterial efficacy of the combination CBD + PB against multidrug-resistant and extensively drug-resistant GNB, especially PB-resistant K. pneumoniae, is particularly promising.

Identifiants

pubmed: 35440801
doi: 10.1038/s41598-022-10393-8
pii: 10.1038/s41598-022-10393-8
pmc: PMC9018834
doi:

Substances chimiques

Anti-Bacterial Agents 0
Cannabidiol 19GBJ60SN5
Polymyxin B J2VZ07J96K

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

6454

Informations de copyright

© 2022. The Author(s).

Références

Pendleton, J. N., Gorman, S. P. & Gilmore, B. F. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti. Infect. Ther. 11, 297–308 (2013).
doi: 10.1586/eri.13.12 pubmed: 23458769
Magiorakos, A. P. 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. 18, 268–281 (2012).
doi: 10.1111/j.1469-0691.2011.03570.x pubmed: 21793988
Poirel, L., Jayol, A. & Nordmann, P. Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin. Microbiol. Rev. 30, 557–596 (2017).
doi: 10.1128/CMR.00064-16 pubmed: 28275006 pmcid: 5355641
Tamma, P. D. et al. Infectious Diseases Society of America Guidance on the treatment of extended-spectrum β-lactamase producing enterobacterales (ESBL-E), carbapenem-resistant enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR- P. aer. Clin. Infect. Dis. 72, 1109–1116 (2012).
doi: 10.1093/cid/ciab295
World Health Organization. World Health Organization Model List of Essential Medicines—22nd List. (2021).
Tacconelli, E. et al. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 18, 318–327 (2018).
doi: 10.1016/S1473-3099(17)30753-3 pubmed: 29276051
Barichello, T. et al. Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. Eur. J. Pharmacol. 697, 158–164 (2012).
doi: 10.1016/j.ejphar.2012.09.053 pubmed: 23085269
Crippa, J. A., Guimarães, F. S., Campos, A. C. & Zuardi, A. W. Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age. Front. Immunol. 9, 1–16 (2018).
doi: 10.3389/fimmu.2018.02009
Cassano, T. et al. From Cannabis sativa to cannabidiol: Promising therapeutic candidate for the treatment of neurodegenerative diseases. Front. Pharmacol. 11, 1–10 (2020).
doi: 10.3389/fphar.2020.00124
Kosgodage, U. S. et al. Cannabidiol is a novel modulator of bacterial membrane vesicles. Front. Cell. Infect. Microbiol. 9, 1–13 (2019).
doi: 10.3389/fcimb.2019.00324
Appendino, G. et al. Antibacterial cannabinoids from Cannabis sativa: A structure-activity study. J. Nat. Prod. 71, 1427–1430 (2008).
doi: 10.1021/np8002673 pubmed: 18681481
van Klingeren, B. & ten Ham, M. Antibacterial activity of Δ9-tetrahydrocannabinol and cannabidiol. Antonie Van Leeuwenhoek 42, 9–12 (1976).
doi: 10.1007/BF00399444 pubmed: 1085130
Andrade, L. N. et al. Antimicrobial activity of cannabidiol against Eskape pathogens: Inhibitory and bactericidal activity against vancomycin-resistant Enterococcus faecium, vancomycin-intermediate Staphylococcus aureus, and methicillin-resistant S. aureus. in ASM MICROBE 2018 (2018).
Farha, M. A. et al. Uncovering the hidden antibiotic potential of cannabis. ACS Infect. Dis. 6, 338–346 (2020).
doi: 10.1021/acsinfecdis.9b00419 pubmed: 32017534
Martinenghi, L. D., Jønsson, R., Lund, T. & Jenssen, H. Isolation, purification, and antimicrobial characterization of cannabidiolic acid and cannabidiol from Cannabis sativa L. Biomolecules 10, 1–16 (2020).
doi: 10.3390/biom10060900
Blaskovich, M. A. T. et al. The antimicrobial potential of cannabidiol. Commun. Biol. https://doi.org/10.1038/s42003-020-01530-y (2021).
doi: 10.1038/s42003-020-01530-y pubmed: 33469147 pmcid: 7815910
Abichabki, N. et al. Cannabidiol synergic antimicrobial activity combined with polymyxin B (PB) against PB susceptible and resistant Gram-Negative bacilli. in 30th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2020 (2020).
Sullivan, G. J., Delgado, N. N., Maharjan, R. & Cain, A. K. How antibiotics work together: Molecular mechanisms behind combination therapy. Curr. Opin. Microbiol. 57, 31–40 (2020).
doi: 10.1016/j.mib.2020.05.012 pubmed: 32619833
Zhu, M., Tse, M. W., Weller, J., Chen, J. & Blainey, P. C. The future of antibiotics begins with discovering new combinations. Ann. N. Y. Acad. Sci. 1496, 82–96 (2021).
doi: 10.1111/nyas.14649 pubmed: 34212403
Yim, G., Huimi Wang, H. & Davies, J. The truth about antibiotics. Int. J. Med. Microbiol. 296, 163–170 (2006).
doi: 10.1016/j.ijmm.2006.01.039 pubmed: 16503195
Baquero, F. & Coque, T. M. Widening the spaces of selection: Evolution along sublethal antimicrobial gradients. MBio 5, 5–7 (2014).
doi: 10.1128/mBio.02270-14
Baquero, F. et al. Evolutionary pathways and trajectories in antibiotic resistance. Clin. Microbiol. Rev. 34(4), e0005019. https://doi.org/10.1128/CMR.00050-19 (2021).
EUCAST. Clinical breakpoints—Bacteria (v 11.0). (2021).
CLSI. CLSI M100-ED30:2020 Performance Standards for Antimicrobial Susceptibility Testing, 30th Edition. Clinical & Laboratory Standards Institute. http://em100.edaptivedocs.net/dashboard.aspx . Accessed 26 Oct 2021 (2020).
Foerster, S., Desilvestro, V., Hathaway, L. J., Althaus, C. L. & Unemo, M. A new rapid resazurin-based microdilution assay for antimicrobial susceptibility testing of Neisseria gonorrhoeae. J. Antimicrob. Chemother. 72, 1961–1968 (2017).
doi: 10.1093/jac/dkx113 pubmed: 28431096 pmcid: 5890744
EUCAST. Antimicrobial susceptibility testing. https://eucast.org/ast_of_bacteria/ . Accessed 26 Oct 2021 (2021).
Palmeiro, J. K. et al. Molecular epidemiology of multidrug-resistant klebsiella pneumoniae Isolates in a Brazilian Tertiary Hospital. Front. Microbiol. 10, 1–11 (2019).
doi: 10.3389/fmicb.2019.01669
Brennan-Krohn, T., Pironti, A. & Kirby, J. E. Synergistic activity of colistin-containing combinations. Antimicrob. Agents Chemother. 62, 1–11 (2018).
doi: 10.1128/AAC.00873-18
Fernandes, M. R. et al. Silent dissemination of colistin-resistant Escherichia coli in South America could contribute to the global spread of the mcr-1 gene. Eurosurveillance 21, 1–6 (2016).
doi: 10.2807/1560-7917.ES.2016.21.17.30214
Andrade, L. N. et al. Expansion and evolution of a virulent, extensively drug-resistant (polymyxin B-resistant), QnrS1-, CTX-M-2-, and KPC-2-producing Klebsiella pneumoniae ST11 international high-risk clone. J. Clin. Microbiol. 52, 2530–2535 (2014).
doi: 10.1128/JCM.00088-14 pubmed: 24808234 pmcid: 4097695
EUCAST. Media preparation for EUCAST disk diffusion testing and for determination of MIC values by the broth microdilution method. 1–5 (2020).
Preston, A., Mandrell, R. E., Gibson, B. W. & Apicella, M. A. The lipooligosaccharides of pathogenic gram-negative bacteria. Crit. Rev. Microbiol. 22, 139–180 (1996).
doi: 10.3109/10408419609106458 pubmed: 8894399
Peng, D., Hong, W., Choudhury, B. P., Carlson, R. W. & Gu, X. X. Moraxella catarrhalis bacterium without endotoxin, a potential vaccine candidate. Infect. Immun. 73, 7569–7577 (2005).
doi: 10.1128/IAI.73.11.7569-7577.2005 pubmed: 16239560 pmcid: 1273912
Vinogradov, E. V., Duus, J., Brade, H. & Holst, O. The structure of the carbohydrate backbone of the lipopolysaccharide from Acinetobacter baumannii strain ATCC 19606. Eur. J. Biochem. 269, 422–430 (2002).
doi: 10.1046/j.0014-2956.2001.02647.x pubmed: 11856300
Guzmán, M. Cannabinoids: Potential anticancer agents. Nat. Rev. Cancer 3, 745–755 (2003).
doi: 10.1038/nrc1188 pubmed: 14570037
Guard, S. E. et al. Multi-omic analysis reveals cannabidiol disruption of cholesterol homeostasis in human cell lines. 1–42 (2020). https://doi.org/10.1242/dev.180224 .
Abichabki, N. et al. In Vitro Antibacterial Efficacy of Cannabidiol Plus Polymyxin B: Mixed and Together Against Multidrug-resistant and Polymyxin B-resistant Gram-negative Bacilli. in World Microbe Forum Abstracts (2021).
BrCAST. Tabelas de pontos de corte para interpretação de CIMs e diâmetros de halos. Braz. Comm. Antimicrob. Susceptibility Test. BrCAST 11, 37–40 (2021).
Lv, Y. et al. Systematic mutation analysis of two-component signal transduction systems reveals EsrA-EsrB and PhoP-PhoQ as the major virulence regulators in Edwardsiella tarda. Vet. Microbiol. 157, 190–199 (2012).
doi: 10.1016/j.vetmic.2011.12.018 pubmed: 22227416
Falagas, M. E., Kasiakou, S. K. & Saravolatz, L. D. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin. Infect. Dis. 40, 1333–1341 (2005).
doi: 10.1086/429323 pubmed: 15825037
Brennan-Krohn, T. & Kirby, J. E. When one drug is not enough: Context, methodology, and future prospects in antibacterial synergy testing. Clin. Lab. Med. 39, 345–358 (2019).
doi: 10.1016/j.cll.2019.04.002 pubmed: 31383261 pmcid: 6686866
Lamers, R. P., Cavallari, J. F. & Burrows, L. L. The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAΒN) permeabilizes the outer membrane of gram-negative bacteria. PLoS ONE 8, 1–7 (2013).
doi: 10.1371/journal.pone.0060666
U. S. Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd . Accessed 26 Oct 2021 (2020).
European Medicines Agency. An overview of Epidyolex and why it is authorised in the EU. (2019).
ANVISA. Anvisa autoriza primeiro produto à base de Cannabis. Agência Nacional de Vigilância Sanitária https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2020/anvisa-autoriza-primeiro-produto-a-base-de-cannabis . Accessed 26 Oct 2021 (2020).
Perucca, E. & Bialer, M. Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications. CNS Drugs https://doi.org/10.1007/s40263-020-00741-5 (2020).
doi: 10.1007/s40263-020-00741-5 pubmed: 32504461
Millar, S. A., Maguire, R. F., Yates, A. S. & O’Sullivan, S. E. Towards better delivery of cannabidiol (CBD). Pharmaceuticals 13, 219 (2020).
doi: 10.3390/ph13090219 pmcid: 7558665
Mechoulam, R., Parker, L. A. & Gallily, R. Cannabidiol: An overview of some pharmacological aspects. J. Clin. Pharmacol. 42, 11–19 (2002).
doi: 10.1002/j.1552-4604.2002.tb05998.x
Taylor, L., Gidal, B., Blakey, G., Tayo, B. & Morrison, G. A phase I, randomized, double—blind, placebo—controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs 32, 1053–1067 (2018).
doi: 10.1007/s40263-018-0578-5 pubmed: 30374683 pmcid: 6223703
Makabenta, J. M. V. et al. Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections. Nat. Rev. Microbiol. 19, 23–36 (2021).
doi: 10.1038/s41579-020-0420-1 pubmed: 32814862
Fraguas-Sánchez, A. I., Fernández-Carballido, A., Martin-Sabroso, C. & Torres-Suárez, A. I. Stability characteristics of cannabidiol for the design of pharmacological, biochemical and pharmaceutical studies. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 1150, 122188 (2020).
doi: 10.1016/j.jchromb.2020.122188
Zheng, W., Sun, W. & Simeonov, A. Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br. J. Pharmacol. 175, 181–191 (2018).
doi: 10.1111/bph.13895 pubmed: 28685814
Jarow, J. P., Lurie, P., Ikenberry, S. C. & Lemery, S. Overview of FDA’s expanded access program for investigational drugs. Ther. Innov. Regul. Sci. 51, 177–179 (2017).
doi: 10.1177/2168479017694850 pubmed: 28553565 pmcid: 5443564
Clímaco, E. C. et al. Clonal complexes 104, 109 and 113 playing a major role in the dissemination of OXA-carbapenemase-producing Acinetobacter baumannii in Southeast Brazil. Infect. Genet. Evol. 19, 127–133 (2013).
doi: 10.1016/j.meegid.2013.06.024 pubmed: 23838284
Galetti, R. et al. Genomic diversification and virulence features in SPM-1-producing Pseudomonas aeruginosa 13 years later. Diagn. Microbiol. Infect. Dis. 82, 179–180 (2015).
doi: 10.1016/j.diagmicrobio.2015.02.011 pubmed: 25824724
Palomino, J. et al. Resazurin microtiter assay plate: Simple and inexpensive method for detection of drug resistance in mycobacterium tuberculosis. Antimicrobail. Agents Chemother. 46, 2720–2722 (2002).
doi: 10.1128/AAC.46.8.2720-2722.2002
Sundaramoorthy, N. S., Sivasubramanian, A. & Nagarajan, S. Simultaneous inhibition of MarR by salicylate and efflux pumps by curcumin sensitizes colistin resistant clinical isolates of Enterobacteriaceae. Microb. Pathog. 148, 104445 (2020).
doi: 10.1016/j.micpath.2020.104445 pubmed: 32814143
Mahmood, Y., Jamshidi, S., Mark Sutton, J. & Rahman, M. Current advances in developing inhibitors of bacterial multidrug efflux pumps. Curr. Med. Chem. 23, 1062–1081 (2016).
doi: 10.2174/0929867323666160304150522 pubmed: 26947776 pmcid: 5425656
Doern, C. D. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J. Clin. Microbiol. 52, 4124–4128 (2014).
doi: 10.1128/JCM.01121-14 pubmed: 24920779 pmcid: 4313275
Brennan-Krohn, T. & Kirby, J. E. Antimicrobial synergy testing by the inkjet printer-assisted automated checkerboard array and the manual time-kill method. J. Vis. Exp. 2019, 2–3 (2019).

Auteurs

Nathália Abichabki (N)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Luísa V Zacharias (LV)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Natália C Moreira (NC)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Fernando Bellissimo-Rodrigues (F)

Department of Social Medicine, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.

Fernanda L Moreira (FL)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Jhohann R L Benzi (JRL)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Tânia M C Ogasawara (TMC)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Joseane C Ferreira (JC)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Camila M Ribeiro (CM)

Department of Biological Sciences, School of Pharmaceutical Sciences (FCF), São Paulo State University (UNESP), Araraquara, SP, Brazil.

Fernando R Pavan (FR)

Department of Biological Sciences, School of Pharmaceutical Sciences (FCF), São Paulo State University (UNESP), Araraquara, SP, Brazil.

Leonardo R L Pereira (LRL)

Department of Pharmaceutical Sciences (DCF), School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.

Guilherme T P Brancini (GTP)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Gilberto Ú L Braga (GÚL)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Antonio W Zuardi (AW)

Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
National Institute of Science and Technology for Translational Medicine (INCT-TM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasília, DF, Brazil.

Jaime E C Hallak (JEC)

Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
National Institute of Science and Technology for Translational Medicine (INCT-TM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasília, DF, Brazil.

José A S Crippa (JAS)

Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
National Institute of Science and Technology for Translational Medicine (INCT-TM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasília, DF, Brazil.

Vera L Lanchote (VL)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Rafael Cantón (R)

Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.

Ana Lúcia C Darini (ALC)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil.

Leonardo N Andrade (LN)

Department of Clinical Analyses, Toxicology and Food Science (DACTB), School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP), University of São Paulo (USP), Av. do Café, s/nº, Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil. leonardo@fcfrp.usp.br.

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