Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing
Abstract
:1. Introduction
2. Repurposing Anti-Infectives against M. tuberculosis
3. Host-Directed Therapies (HDT) against M. tuberculosis
3.1. HDTs Based on the Induction of Autophagy and Phagosome Maturation
3.2. Host Genes as Targets for HDTs
4. General Limitations of Drug Repurposing
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Russell, D.G. Mycobacterium tuberculosis and the intimate discourse of a chronic infection. Immunol. Rev. 2011, 240, 252–268. [Google Scholar]
- Dheda, K.; Barry, C.E.; Maartens, G. Tuberculosis. Lancet 2015, 6736, 1–15. [Google Scholar]
- Wallis, R.S.; Maeurer, M.; Mwaba, P.; Chakaya, J.; Rustomjee, R.; Migliori, G.B.; Marais, B.; Schito, M. Tuberculosis—Advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers. Lancet Infect. Dis. 2016, 16, e34–e46. [Google Scholar]
- Liao, Z.; Zhang, X.; Zhang, Y.; Peng, D. Seasonality and trend forecasting of tuberculosis incidence in Chongqing, China. Interdiscip. Sci. Comput. Life Sci. 2019, 11, 77–85. [Google Scholar]
- Bussi, C.; Gutierrez, M.G. Mycobacterium tuberculosis infection of host cells in space and time. FEMS Microbiol. Rev. 2019, 43, 341–361. [Google Scholar]
- Hare, N.J.; Lee, L.Y.; Loke, I.; Britton, W.J.; Saunders, B.M.; Thaysen-Andersen, M. Mycobacterium tuberculosis infection manipulates the glycosylation machinery and the N -glycoproteome of human macrophages and their microparticles. J. Proteome Res. 2016, 16, 247–263. [Google Scholar]
- Maertzdorf, J.; Repsilber, D.; Parida, S.K.; Stanley, K.; Roberts, T.; Black, G.; Walzl, G.; Kaufmann, S.H.E. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun. 2011, 12, 15–22. [Google Scholar]
- van Tong, H.; Velavan, T.P.; Thye, T.; Meyer, C.G. Human genetic factors in tuberculosis: An update. Trop. Med. Int. Health 2017, 22, 1063–1071. [Google Scholar]
- Wang, Z.; Arat, S.; Magid-Slav, M.; Brown, J.R. Meta-analysis of human gene expression in response to Mycobacterium tuberculosis infection reveals potential therapeutic targets. BMC Syst. Biol. 2018, 12, 1–18. [Google Scholar]
- Cumming, B.M.; Steyn, A.J.C. Metabolic plasticity of central carbon metabolism protects mycobacteria. Proc. Natl. Acad. Sci. USA 2015, 112, 13135–13136. [Google Scholar]
- Rahman, M.A.; Cumming, B.M.; Addicott, K.W.; Pacl, H.T.; Russell, S.L.; Nargan, K.; Naidoo, T.; Ramdial, P.K.; Adamson, J.H.; Wang, R.; et al. Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis. Proc. Natl. Acad. Sci. USA 2020, 117, 6663–6674. [Google Scholar]
- Varma, D.M.; Zahid, M.S.H.; Bachelder, E.M.; Ainslie, K.M. Formulation of host-targeted therapeutics against bacterial infections. Transl. Res. 2020, 220, 1–16. [Google Scholar] [CrossRef]
- Kaur, D.; Mathew, S.; Nair, C.G.S.; Begum, A.; Jainanarayan, A.K.; Sharma, M.; Brahmachari, S.K. Structure based drug discovery for designing leads for the non-toxic metabolic targets in multi drug resistant Mycobacterium tuberculosis. J. Transl. Med. 2017, 15, 1–16. [Google Scholar]
- Konreddy, A.K.; Rani, G.U.; Lee, K.; Choi, Y. Recent drug-repurposing-driven advances in the discovery of novel antibiotics. Curr. Med. Chem. 2018, 26, 5363–5388. [Google Scholar]
- Battah, B.; Chemi, G.; Butini, S.; Campiani, G.; Brogi, S.; Delogu, G.; Gemma, S. A repurposing approach for uncovering the anti-tubercular activity of FDA-approved drugs with potential multi-targeting profiles. Molecules 2018, 24, 1–12. [Google Scholar]
- An, Q.; Li, C.; Chen, Y.; Deng, Y.; Yang, T.; Luo, Y. Repurposed drug candidates for antituberculosis therapy. Eur. J. Med. Chem. 2020, 192, 1–18. [Google Scholar] [CrossRef]
- Mehmood, A.; Khan, M.T.; Kaushik, A.C.; Khan, A.S.; Irfan, M.; Wei, D.Q. Structural dynamics behind clinical mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis associated with pyrazinamide resistance. Front. Bioeng. Biotechnol. 2019, 7, 1–16. [Google Scholar]
- Tahir Khan, M.; Chinnasamy, S.; Cui, Z.; Irfan, M.; Wei, D.-Q. Mechanistic analysis of A46V, H57Y, and D129N in pyrazinamidase associated with pyrazinamide resistance. Saudi J. Biol. Sci. 2020. [Google Scholar] [CrossRef]
- Pule, C.M.; Sampson, S.L.; Warren, R.M.; Black, P.A.; Van Helden, P.D.; Victor, T.C.; Louw, G.E. Efflux pump inhibitors: Targeting mycobacterial efflux systems to enhance TB therapy. J. Antimicrob. Chemother. 2016, 71, 17–26. [Google Scholar]
- Fischbach, M.A.; Walsh, C.T. Antibiotics for emerging pathogens. Science 2009, 325, 1089–1093. [Google Scholar]
- Chiang, C.Y.; Uzoma, I.; Moore, R.T.; Gilbert, M.; Duplantier, A.J.; Panchal, R.G. Mitigating the impact of antibacterial drug resistance through host-directed therapies: Current progress, outlook, and challenges. MBio 2018, 9, e01932-17. [Google Scholar]
- Mishra, A.; Mamidi, A.S.; Rajmani, R.S.; Ray, A.; Roy, R.; Surolia, A. An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy. EMBO Mol. Med. 2018, 10, 1–21. [Google Scholar]
- Coelho, T.S.; Halicki, P.C.B.; Silva, L.; de Vicenti, M.J.R.; Gonçalves, B.L.; da Silva, A.P.E.; Ramos, D.F. Metal-based antimicrobial strategies against intramacrophage Mycobacterium tuberculosis. Lett. Appl. Microbiol. 2020, 1–8. [Google Scholar] [CrossRef]
- Pacios, O.; Blasco, L.; Bleriot, I.; Fernández-García, L.; González Bardanca, M.; Ambroa, A.; López, M.; Bou, G.; Tomás, M. Strategies to combat multidrug-resistant and persistent infectious diseases. Antibiotics 2020, 9, 1–20. [Google Scholar]
- Salie, S.; Labuschagné, A.; Walters, A.; Geyer, S.; Jardine, A.; Jacobs, M.; Hsu, N.J. In vitro and in vivo toxicity evaluation of non-neuroleptic phenothiazines, antitubercular drug candidates. Regul. Toxicol. Pharmacol. 2019, 109, 104508. [Google Scholar]
- Naicker, N.; Sigal, A.; Naidoo, K. Metformin as host-directed therapy for TB treatment: Scoping review. Front. Microbiol. 2020, 11, 1–11. [Google Scholar]
- Miró-Canturri, A.; Ayerbe-Algaba, R.; Smani, Y. Drug repurposing for the treatment of bacterial and fungal infections. Front. Microbiol. 2019, 10, 10. [Google Scholar]
- Guerra-De-Blas, P.D.C.; Bobadilla-Del-Valle, M.; Sada-Ovalle, I.; Estrada-García, I.; Torres-González, P.; López-Saavedra, A.; Guzmán-Beltrán, S.; Ponce-de-León, A.; Sifuentes-Osornio, J. Simvastatin enhances the immune response against Mycobacterium tuberculosis. Front. Microbiol. 2019, 10, 1–14. [Google Scholar]
- Tiberi, S.; du Plessis, N.; Walzl, G.; Vjecha, M.J.; Rao, M.; Ntoumi, F.; Mfinanga, S.; Kapata, N.; Mwaba, P.; McHugh, T.D.; et al. Tuberculosis: Progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect. Dis. 2018, 18, e183–e198. [Google Scholar]
- Bilaçeroǧlu, S.; Perim, K.; Büyükşirin, M.; Çelikten, E. Prednisolone: A beneficial and safe adjunct to antituberculosis treatment? A randomized controlled trial. Int. J. Tuberc. Lung Dis. 1999, 3, 47–54. [Google Scholar]
- Gengenbacher, M.; Zimmerman, M.D.; Sarathy, J.P.; Kaya, F.; Wang, H.; Mina, M.; Carter, C.; Hossen, M.A.; Su, H.; Trujillo, C.; et al. Tissue distribution of doxycycline in animal models of tuberculosis. Antimicrob. Agents Chemother. 2020, 64, 1–11. [Google Scholar]
- Kim, J.H.; O’Brien, K.M.; Sharma, R.; Boshoff, H.I.M.; Rehren, G.; Chakraborty, S.; Wallach, J.B.; Monteleone, M.; Wilson, D.J.; Aldrich, C.C.; et al. A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence. Proc. Natl. Acad. Sci. USA 2013, 110, 19095–19100. [Google Scholar]
- Ranjbar, S.; Haridas, V.; Nambu, A.; Jasenosky, L.D.; Sadhukhan, S.; Ebert, T.S.; Hornung, V.; Cassell, G.H.; Falvo, J.V.; Goldfeld, A.E. Cytoplasmic RNA sensor pathways and nitazoxanide broadly inhibit intracellular Mycobacterium tuberculosis growth. iScience 2019, 22, 299–313. [Google Scholar]
- Jasenosky, L.D.; Cadena, C.; Mire, C.E.; Borisevich, V.; Haridas, V.; Ranjbar, S.; Nambu, A.; Bavari, S.; Soloveva, V.; Sadukhan, S.; et al. The FDA-approved oral drug nitazoxanide amplifies host antiviral responses and inhibits ebola virus. iScience 2019, 19, 1279–1290. [Google Scholar]
- Ouyang, Q.; Zhang, K.; Lin, D.; Feng, C.G.; Cai, Y.; Chen, X. Bazedoxifene suppresses intracellular Mycobacterium tuberculosis growth by enhancing autophagy. mSphere 2020, 5, 1–10. [Google Scholar]
- Hu, Y.; Wen, Z.; Liu, S.; Cai, Y.; Guo, J.; Xu, Y.; Lin, D.; Zhu, J.; Li, D.; Chen, X. Ibrutinib suppresses intracellular Mycobacterium tuberculosis growth by inducing macrophage autophagy. J. Infect. 2020, 80, e19–e26. [Google Scholar]
- Torfs, E.; Piller, T.; Cos, P.; Cappoen, D. Opportunities for overcoming Mycobacterium tuberculosis drug resistance: Emerging mycobacterial targets and host-directed therapy. Int. J. Mol. Sci. 2019, 20, 2868. [Google Scholar]
- Campbell, G.R.; Spector, S.A. Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy. PLoS Pathog. 2012, 8, e1002689. [Google Scholar]
- Wallis, R.S.; Zumla, A. Vitamin D as adjunctive host-directed therapy in tuberculosis: A systematic review. Open Forum Infect. Dis. 2016, 3, 1–7. [Google Scholar]
- Kang, M.; Shi, J.; Peng, N.; He, S. MicrornarnaRNA-211 promotes non-small-cell lung cancer proliferation and invasion by targeting MxA. Onco. Targets. Ther. 2017, 10, 5667–5675. [Google Scholar]
- Ordonez, A.A.; Abhishek, S.; Singh, A.K.; Klunk, M.H.; Azad, B.B.; Aboagye, E.O.; Carroll, L.; Jain, S.K. Caspase-based PET for evaluating pro-apoptotic treatments in a tuberculosis mouse model. Mol. Imaging Biol. 2020, 1–6. [Google Scholar] [CrossRef]
- Moradi, M.; Gholipour, H.; Sepehri, H.; Attari, F.; Delphi, L.; Arefian, E. Flavonoid calycopterin triggers apoptosis in triple-negative and ER-positive human breast cancer cells through activating different patterns of gene expression. Arch. Exp. Pathol. Pharmakol. 2020. [Google Scholar] [CrossRef]
- Nijjar, J.S.; Tindell, A.; Mcinnes, I.B.; Siebert, S. Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis. Rheumatology 2013, 52, 1556–1562. [Google Scholar]
- Mourenza, Á.; Gil, J.A.; Mateos, L.M.; Letek, M. A novel screening strategy reveals ROS—Generating antimicrobials that act synergistically against the intracellular veterinary pathogen Rhodococcus equi. Antioxidants 2020, 9, 114. [Google Scholar]
- Mourenza, Á.; Gil, J.A.; Mateos, M.; Letek, M. Oxidative stress-generating antimicrobials, a novel strategy to overcome antibacterial resistance. Antioxidants 2020, 9, 361. [Google Scholar]
- Bhaskar, A.; Chawla, M.; Mehta, M.; Parikh, P.; Chandra, P.; Bhave, D.; Kumar, D.; Carroll, K.S.; Singh, A. Reengineering redox sensitive GFP to measure mycothiol redox potential of Mycobacterium tuberculosis during infection. PLoS Pathog. 2014, 10, e1003902. [Google Scholar]
- Nair, R.R.; Sharan, D.; Sebastian, J.; Swaminath, S.; Ajitkumar, P. Heterogeneity of ROS levels in antibiotic-exposed mycobacterial subpopulations confers differential susceptibility. Microbiology 2019, 165, 668–682. [Google Scholar]
- Lu, J.; Vlamis-gardikas, A.; Kandasamy, K.; Zhao, R.; Gustafsson, T.N.; Engstrand, L.; Hoffner, S.; Engman, L.; Holmgren, A. Inhibition of bacterial thioredoxin reductase: An antibiotic mechanism targeting bacteria lacking glutathione. FASEB J. 2013, 27, 1394–1403. [Google Scholar]
- Bravo-Santano, N.; Behrends, V.; Letek, M. Host-targeted therapeutics against multidrug resistant intracellular Staphylococcus aureus. Antibiotics 2019, 8, 241. [Google Scholar]
- Zumla, A.; Maeurer, M. Host-directed therapies for multidrug resistant tuberculosis. Int. J. Mycobacteriology 2016, 5, S21–S22. [Google Scholar]
- Zumla, A.; Maeurer, M.; Zumla, A.; Chakaya, J.; Hoelscher, M.; Ntoumi, F.; Rustomjee, R.; Vilaplana, C.; Yeboah-Manu, D.; Rasolofo, V.; et al. Host-directed therapies for tackling multi-drug resistant tuberculosis: Learning from the pasteur-bechamp debates. Clin. Infect. Dis. 2015, 61, 1432–1438. [Google Scholar]
- Mishra, R.; Krishan, S.; Siddiqui, A.N.; Kapur, P.; Khayyam, K.U.; Sharma, M. Potential role of adjuvant drugs on efficacy of first line oral antitubercular therapy: Drug repurposing. Tuberculosis 2020, 120, 101902. [Google Scholar]
- Odingo, J.; Bailey, M.A.; Files, M.; Early, J.V.; Alling, T.; Dennison, D.; Bowman, J.; Dalai, S.; Kumar, N.; Cramer, J.; et al. In vitro evaluation of novel nitazoxanide derivatives against Mycobacterium tuberculosis. ACS Omega 2017, 2, 5873–5890. [Google Scholar]
- Yogalingam, G.; Pendergast, A.M. Abl kinases regulate autophagy by promoting the trafficking and function of lysosomal components. J. Biol. Chem. 2008, 283, 35941–35953. [Google Scholar]
- Paik, S.; Kim, J.K.; Chung, C.; Jo, E.K. Autophagy: A new strategy for host-directed therapy of tuberculosis. Virulence 2019, 10, 448–459. [Google Scholar]
- Divangahi, M.; Chen, M.; Gan, H.; Dejardins, D.; Tyler, T.; Lee, D.M.; Fortune, S.; Behar, S.M.; Remold, H.G. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair Maziar. Nat. Immunol. 2009, 10, 899–906. [Google Scholar]
- Philips, J.A.; Ernst, J.D. Tuberculosis pathogenesis and immunity. Annu. Rev. Pathol. Mech. Dis. 2012, 7, 353–384. [Google Scholar]
- Shi, Q.; Wang, J.; Yang, Z.; Liu, Y. CircAGFG1modulates autophagy and apoptosis of macrophages infected by Mycobacterium tuberculosis via the Notch signaling pathway. Ann. Transl. Med. 2020, 8, 645. [Google Scholar]
- Bah, A.; Sanicas, M.; Nigou, J.; Guilhot, C.; Astarie-Dequeker, C.; Vergne, I. The lipid virulence factors of Mycobacterium tuberculosis exert multilayered control over autophagy-related pathways in infected human macrophages. Cells 2020, 9, 666. [Google Scholar]
- Yuan, Q.; Chen, H.; Yang, Y.; Fu, Y.; Yi, Z. miR-18a promotes Mycobacterial survival in macrophages via inhibiting autophagy by down-regulation of ATM. J. Cell. Mol. Med. 2020, 24, 2004–2012. [Google Scholar]
- Fang, F.; Ge, Q.; Li, R.; Lv, J.; Zhang, Y.; Feng, A.; Kelly, G.T.; Wang, H.; Wang, X.; Song, C.; et al. LPS restores protective immunity in macrophages against Mycobacterium tuberculosis via autophagy. Mol. Immunol. 2020, 124, 18–24. [Google Scholar]
- Parihar, S.P.; Guler, R.; Khutlang, R.; Lang, D.M.; Hurdayal, R.; Mhlanga, M.M.; Suzuki, H.; Marais, A.D.; Brombacher, F. Statin therapy reduces the Mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J. Infect. Dis. 2014, 209, 754–763. [Google Scholar]
- Sogi, K.M.; Lien, K.A.; Johnson, J.R.; Krogan, N.J.; Stanley, S.A. The tyrosine kinase inhibitor gefitinib restricts Mycobacterium tuberculosis growth through increased lysosomal biogenesis and modulation of cytokine signaling. ACS Infect. Dis. 2017, 3, 564–574. [Google Scholar]
- Dallmann-Sauer, M.; Correa-Macedo, W.; Schurr, E. Human genetics of mycobacterial disease. Mamm. Genome 2018, 29, 523–538. [Google Scholar]
- Zhan, W.; Hsu, H.-C.; Morgan, T.; Ouellette, T.; Burns-Huang, K.; Hara, R.; Wright, A.G.; Imaeda, T.; Okamoto, R.; Sato, K.; et al. Selective phenylimidazole-based inhibitors of the Mycobacterium tuberculosis proteasome. J. Med. Chem. 2019, 62, 9246–9253. [Google Scholar]
- Mcnab, F.; Mayer-barber, K.; Sher, A.; Wack, A.; Garra, A.O. Type I interferons in infectious disease. Nat. Rev. Immunol. 2015, 15, 87–103. [Google Scholar]
- Zhou, X.; Zhang, L.; Lie, L.; Zhang, Z.; Zhu, B.; Yang, J.; Gao, Y.; Li, P.; Huang, Y.; Xu, H.; et al. MxA suppresses TAK1-IKKα/β-NF-κB mediated inflammatory cytokine production to facilitate Mycobacterium tuberculosis infection. J. Infect. 2020, 81, 231–241. [Google Scholar]
- Pedruzzi, G.; Das, P.N.; Rao, K.V.S.; Chatterjee, S. Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model. J. Theor. Biol. 2016, 389, 159–170. [Google Scholar]
- North, T.E.; Goessling, W.; Walkley, C.R.; Lengerke, C.; Kopani, K.R.; Lord, A.M.; Weber, G.J.; Bowman, T.V.; Jang, I.; Fitzgerald, G.A.; et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 2007, 447, 1007–1011. [Google Scholar]
- Lam, A.; Prabhu, R.; Gross, C.M.; Riesenberg, L.A.; Singh, V.; Aggarwal, S. Role of apoptosis and autophagy in tuberculosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 2017, 313, L218–L229. [Google Scholar]
- Sly, L.M.; Hingley-Wilson, S.M.; Reiner, N.E.; McMaster, W.R. Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. J. Immunol. 2003, 170, 430–437. [Google Scholar]
- Lu, N.; Huo, J.L.; Wang, S.; Yuan, X.H.; Liu, H.M. Drug repurposing: Discovery of troxipide analogs as potent antitumor agents. Eur. J. Med. Chem. 2020, 202, 112471. [Google Scholar]
- Härtlova, A.; Herbst, S.; Peltier, J.; Rodgers, A.; Bilkei-Gorzo, O.; Fearns, A.; Dill, B.D.; Lee, H.; Flynn, R.; Cowley, S.A.; et al. LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. EMBO J. 2018, 37, 1–17. [Google Scholar]
- Wallings, R.L.; Tansey, M.G. LRRK2 regulation of immune-pathways and inflammatory disease. Biochem. Soc. Trans. 2019, 47, 1581–1595. [Google Scholar]
- Lee, H.; Flynn, R.; Sharma, I.; Haberman, E.; Carling, P.J.; Nicholls, F.J.; Stegmann, M.; Vowles, J.; Haenseler, W.; Wade-Martins, R.; et al. LRRK2 is recruited to phagosomes and co-recruits RAB8 and RAB10 in human pluripotent stem cell-derived macrophages. Stem Cell Rep. 2020, 14, 940–955. [Google Scholar]
- Korecka, J.A.; Thomas, R.; Hinrich, A.J.; Moskites, A.M.; Macbain, Z.K.; Hallett, P.J.; Isacson, O.; Hastings, M.L. Splice-switching antisense oligonucleotides reduce LRRK2 kinase activity in human LRRK2 transgenic mice. Mol. Ther. Nucleic Acids 2020, 21, 623–635. [Google Scholar]
- Kawatkar, S.P.; Barlaam, B.; Kemmitt, P.; Simpson, I.; Watson, D.; Wang, P.; Lamont, S.; Su, Q.; Boiko, S.; Ikeda, T.; et al. Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase. Bioorganic Med. Chem. Lett. 2020, 30, 127393. [Google Scholar]
- Maier, L.; Pruteanu, M.; Kuhn, M.; Zeller, G.; Telzerow, A.; Anderson, E.E.; Brochado, A.R.; Fernandez, K.C.; Dose, H.; Mori, H.; et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018, 555, 623–628. [Google Scholar]
- Bravo-santano, N.; Stölting, H.; Cooper, F.; Bileckaja, N.; Majstorovic, A.; Ihle, N.; Mateos, L.M.; Calle, Y.; Behrends, V.; Letek, M. Host-directed kinase inhibitors act as novel therapies against intracellular Staphylococcus aureus. Sci. Rep. 2019, 9, 1–12. [Google Scholar]
Repurposed Drugs | Primary Mechanism of Action | Reference |
---|---|---|
Transition metals (Cu2+ and Co2+) | Interfering with urease | [23] |
Eltrombopag Fluvastatin | Inhibition of Zmp1 and PDF | [15] |
Avermectin | Undefined | [24] |
Non-neuroleptic phenothiazines | Undefined | [25] |
Host-directed therapies | Primary Mechanism of Action | Reference |
Metformin | Phagosome–lysosome fusion | [26] |
Simvastatin | HMG-CoA inhibition | [24,27,28] |
Corticoids | Immune system modulation | [29,30] |
Doxycycline | Matrix metalloprotease inhibition | [31,32] |
Nitazoxanide | Activator of defense host genes | [33,34] |
Imatinib Ibrutinib | Autophagy activation | [35,36] |
Gefitinib | EGFR inhibition | [37] |
Vitamin D | Inflammatory host response regulation | [37,38,39] |
Carfilzomib | Host genes inhibition | [9] |
microRNAs | MxA inhibition | [40] |
Cisplatin Calycopterin | Apoptosis activation | [41,42] |
Fostamatinib | LRRK2 and spleen tyrosine kinase inhibition | [43] |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Mourenza, Á.; Gil, J.A.; Mateos, L.M.; Letek, M. Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing. Antibiotics 2020, 9, 550. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090550
Mourenza Á, Gil JA, Mateos LM, Letek M. Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing. Antibiotics. 2020; 9(9):550. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090550
Chicago/Turabian StyleMourenza, Álvaro, José A. Gil, Luis M. Mateos, and Michal Letek. 2020. "Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing" Antibiotics 9, no. 9: 550. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090550