Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Mini-Review Article

Bedaquiline in Drug-Resistant Tuberculosis: A Mini-Review

Author(s): Baljinder Singh*

Volume 16, Issue 3, 2023

Published on: 27 August, 2022

Page: [243 - 253] Pages: 11

DOI: 10.2174/1874467215666220421130707

Price: $65


Mycobacterium tuberculosis causes a contagious pulmonary disease with a high mortality rate in developing countries. However, the recommendation of DOTS (approved by WHO) was effective in treating tuberculosis, but nowadays, resistance from the first line (MDR-TB) and the second line (XDR-TB) drugs is highly common. Whereas, the resistance is a result of factors like poor patient constancy due to the long duration of therapy and co-infection with HIV. The approval of bedaquiline under an accelerated program for the treatment of MDR-TB has revealed its effectiveness in clinical trials as a therapeutic novel molecule. BDQ selectively inhibits the ATP synthase of bacterium and reduces ATP production. Additionally, the poor pharmacokinetic properties raised provocations in the MDR therapy, but the use of targeted drug delivery can solve the hurdles. While the preclinical and clinical studies included in this review are strongly suggesting the usefulness of BDQ in MDR-TB and XDR-TB, the repurposing of different drug classes in resistant TB is opening new opportunities to manage the disease conditions. In this review, we have summarized the examples of pipeline drugs and repurposed molecules with preclinical formulation developments.

Keywords: Bedaquiline, mycobacterium tuberculosis, resistant-TB, repurposed drugs, preclinical, ATP production.

Graphical Abstract
Saravanabavan, N.; Shanmuganathan, P.; Kumarappan, M. Bedaquiline: A Mini Review. Ann SBV., 2020, 8(1), 2-4.
Corbett, E.L.; Watt, C.J.; Walker, N.; Maher, D.; Williams, B.G.; Raviglione, M.C.; Dye, C. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic. Arch. Intern. Med., 2003, 163(9), 1009-1021.
[] [PMID: 12742798]
Rodriguez-Takeuchi, S.Y.; Renjifo, M.E.; Medina, F.J. Extrapulmonary tuberculosis: Pathophysiology and imaging findings. Radiographics, 2019, 39(7), 2023-2037.
[] [PMID: 31697616]
Lange, C.; Chesov, D.; Heyckendorf, J.; Leung, C.C.; Udwadia, Z.; Dheda, K. Drug-resistant tuberculosis: An update on disease burden, diagnosis and treatment. Respirology, 2018, 23(7), 656-673.
[] [PMID: 29641838]
Nguyen, L. Antibiotic resistance mechanisms in M. tuberculosis: An update. Arch. Toxicol., 2016, 90(7), 1585-1604.
[] [PMID: 27161440]
Sandhu, G.K. Tuberculosis: Current situation, challenges and overview of its control programs in India. J. Glob. Infect. Dis., 2011, 3(2), 143-150.
[] [PMID: 21731301]
WHO G.. Global tuberculosis report 2020. Glob. Tuberc. Rep., 2020.
Chakaya, J.; Khan, M.; Ntoumi, F.; Aklillu, E.; Fatima, R.; Mwaba, P.; Kapata, N.; Mfinanga, S.; Hasnain, S.E.; Katoto, P.D.; Bulabula, A.N. Global tuberculosis report 2020-reflections on the global tb burden, treatment and prevention efforts; IJID, 2020.
Basaraba, R.J. Experimental tuberculosis: The role of comparative pathology in the discovery of improved tuberculosis treatment strategies. Tuberculosis (Edinb.), 2008, 88(Suppl. 1), S35-S47.
[] [PMID: 18762152]
Wong, E.B.; Cohen, K.A.; Bishai, W.R. Rising to the challenge: New therapies for tuberculosis. Trends Microbiol., 2013, 21(9), 493-501.
[] [PMID: 23764389]
Andries, K.; Verhasselt, P.; Guillemont, J.; Göhlmann, H.W.; Neefs, J.M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science, 2005, 307(5707), 223-227.
[] [PMID: 15591164]
Lakshmanan, M.; Xavier, A.S. Bedaquiline - The first ATP synthase inhibitor against multi drug resistant tuberculosis. J. Young Pharm., 2013, 5(4), 112-115.
[] [PMID: 24563587]
Koul, A.; Dendouga, N.; Vergauwen, K.; Molenberghs, B.; Vranckx, L.; Willebrords, R.; Ristic, Z.; Lill, H.; Dorange, I.; Guillemont, J.; Bald, D.; Andries, K. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat. Chem. Biol., 2007, 3(6), 323-324.
[] [PMID: 17496888]
Biuković G.; Basak, S.; Manimekalai, M.S.; Rishikesan, S.; Roessle, M.; Dick, T.; Rao, S.P.; Hunke, C.; Grüber, G. Variations of subunit varepsilon of the Mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207. Antimicrob. Agents Chemother., 2013, 57(1), 168-176.
[] [PMID: 23089752]
Sarathy, J.P.; Gruber, G.; Dick, T. Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline. Antibiotics (Basel), 2019, 8(4), 261.
[] [PMID: 31835707]
Singh, H.; Natt, N.K.; Garewal, N.; Pugazhenthan, T. Bedaquiline: A new weapon against MDR and XDR-TB. Int. J. Basic Clin. Pharmacol., 2013, 2(2), 96-102.
Haagsma, A.C.; Podasca, I.; Koul, A.; Andries, K.; Guillemont, J.; Lill, H.; Bald, D. Probing the interaction of the diarylquinoline TMC207 with its target mycobacterial ATP synthase. PLoS One, 2011, 6(8), e23575.
[] [PMID: 21858172]
Dooley, K.E.; Park, J.G.; Swindells, S.; Allen, R.; Haas, D.W.; Cramer, Y.; Aweeka, F.; Wiggins, I.; Gupta, A.; Lizak, P.; Qasba, S. Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J. Acquir. Immune Defic. Syndr., 1999, 59(5), 455.
Diacon, A.H.; Donald, P.R.; Pym, A.; Grobusch, M.; Patientia, R.F.; Mahanyele, R.; Bantubani, N.; Narasimooloo, R.; De Marez, T.; van Heeswijk, R.; Lounis, N.; Meyvisch, P.; Andries, K.; McNeeley, D.F. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob. Agents Chemother., 2012, 56(6), 3271-3276.
[] [PMID: 22391540]
Mesens, N.; Steemans, M.; Hansen, E.; Verheyen, G.R.; Van Goethem, F.; Van Gompel, J. Screening for phospholipidosis induced by central nervous drugs: Comparing the predictivity of an in-vitro assay to high throughput in silico assays. Toxicol. In Vitro, 2010, 24(5), 1417-1425.
[] [PMID: 20430096]
Akkerman, O.W.; Odish, O.F.; Bolhuis, M.S.; de Lange, W.C.; Kremer, H.P.; Luijckx, G.J.; van der Werf, T.S.; Alffenaar, J.W. Pharmacokinetics of bedaquiline in cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis. Clin. Infect. Dis., 2016, 62(4), 523-524.
[PMID: 26534926]
Kwon, Y.S.; Koh, W.J. Synthetic investigational new drugs for the treatment of tuberculosis. Expert Opin. Investig. Drugs, 2016, 25(2), 183-193.
[] [PMID: 26576631]
De Matteis, L.; Jary, D.; Lucía, A.; García-Embid, S.; Serrano-Sevilla, I.; Pérez, D.; Ainsa, J.A.; Navarro, F.P.; De la Fuente, J.M. New active formulations against M. tuberculosis: Bedaquiline encapsulation in lipid nanoparticles and chitosan nanocapsules. Chem. Eng. J., 2018, 340, 181-191.
Rawal, T.; Patel, S.; Butani, S. Chitosan nanoparticles as a promising approach for pulmonary delivery of bedaquiline. Eur. J. Pharm. Sci., 2018, 124, 273-287.
[] [PMID: 30176365]
Pamreddy, A.; Baijnath, S.; Naicker, T.; Ntshangase, S.; Mdanda, S.; Lubanyana, H.; Kruger, H.G.; Govender, T. Bedaquiline has potential for targeting tuberculosis reservoirs in the central nervous system. RSC Advances, 2018, 8(22), 11902-11907.
Kaushik, A.; Ammerman, N.C.; Tyagi, S.; Saini, V.; Vervoort, I.; Lachau-Durand, S.; Nuermberger, E.; Andries, K. Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection. Antimicrob. Agents Chemother., 2019, 63(4), e00007-e00019.
[] [PMID: 30745396]
Poh, W.; Ab Rahman, N.; Ostrovski, Y.; Sznitman, J.; Pethe, K.; Loo, S.C.J. Active pulmonary targeting against tuberculosis (TB) via triple-encapsulation of Q203, bedaquiline and superparamagnetic iron oxides (SPIOs) in nanoparticle aggregates. Drug Deliv., 2019, 26(1), 1039-1048.
[] [PMID: 31691600]
Hemelryck, S.V.; Dewulf, J.; Niekus, H.; van Heerden, M.; Ingelse, B.; Holm, R.; Mannaert, E.; Langguth, P. In-vitro evaluation of poloxamer in situ forming gels for bedaquiline fumarate salt and pharmacokinetics following intramuscular injection in rats. Int. J. Pharm. X, 2019, 1, 100016.
[] [PMID: 31517281]
Soria-Carrera, H.; Lucía, A.; De Matteis, L.; Aínsa, J.A.; de la Fuente, J.M.; Martín-Rapún, R. Polypeptidic micelles stabilized with sodium alginate enhance the activity of encapsulated bedaquiline. Macromol. Biosci., 2019, 19(4), e1800397.
[] [PMID: 30645022]
Momin, M.A.M.; Rangnekar, B.; Sinha, S.; Cheung, C.Y.; Cook, G.M.; Das, S.C. Inhalable dry powder of bedaquiline for pulmonary tuberculosis: In-vitro physicochemical characterization, antimicrobial activity and safety studies. Pharmaceutics, 2019, 11(10), 502.
[] [PMID: 31581469]
Diacon, A.H.; Pym, A.; Grobusch, M.P.; de los Rios, J.M.; Gotuzzo, E.; Vasilyeva, I.; Leimane, V.; Andries, K.; Bakare, N.; De Marez, T.; Haxaire-Theeuwes, M.; Lounis, N.; Meyvisch, P.; De Paepe, E.; van Heeswijk, R.P.; Dannemann, B. TMC207-C208 Study Group. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N. Engl. J. Med., 2014, 371(8), 723-732.
[] [PMID: 25140958]
Borisov, S.E.; Dheda, K.; Enwerem, M.; Romero Leyet, R.; D’Ambrosio, L.; Centis, R.; Sotgiu, G.; Tiberi, S.; Alffenaar, J.W.; Maryandyshev, A.; Belilovski, E.; Ganatra, S.; Skrahina, A.; Akkerman, O.; Aleksa, A.; Amale, R.; Artsukevich, J.; Bruchfeld, J.; Caminero, J.A.; Carpena Martinez, I.; Codecasa, L.; Dalcolmo, M.; Denholm, J.; Douglas, P.; Duarte, R.; Esmail, A.; Fadul, M.; Filippov, A.; Davies Forsman, L.; Gaga, M.; Garcia-Fuertes, J.A.; García-García, J.M.; Gualano, G.; Jonsson, J.; Kunst, H.; Lau, J.S.; Lazaro Mastrapa, B.; Teran Troya, J.L.; Manga, S.; Manika, K.; González Montaner, P.; Mullerpattan, J.; Oelofse, S.; Ortelli, M.; Palmero, D.J.; Palmieri, F.; Papalia, A.; Papavasileiou, A.; Payen, M.C.; Pontali, E.; Robalo Cordeiro, C.; Saderi, L.; Sadutshang, T.D.; Sanukevich, T.; Solodovnikova, V.; Spanevello, A.; Topgyal, S.; Toscanini, F.; Tramontana, A.R.; Udwadia, Z.F.; Viggiani, P.; White, V.; Zumla, A.; Migliori, G.B. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study. Eur. Respir. J., 2017, 49(5), 1700387.
[] [PMID: 28529205]
Guglielmetti, L.; Jaspard, M.; Le Dû, D.; Lachâtre, M.; Marigot-Outtandy, D.; Bernard, C.; Veziris, N.; Robert, J.; Yazdanpanah, Y.; Caumes, E.; Fréchet-Jachym, M. French MDR-TB Management Group.Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur. Respir. J., 2017, 49(3), 1601799.
[] [PMID: 28182570]
Mbuagbaw, L.; Guglielmetti, L.; Hewison, C.; Bakare, N.; Bastard, M.; Caumes, E.; Fréchet-Jachym, M.; Robert, J.; Veziris, N.; Khachatryan, N.; Kotrikadze, T.; Hayrapetyan, A.; Avaliani, Z.; Schünemann, H.J.; Lienhardt, C. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg. Infect. Dis., 2019, 25(5), 936-943.
[] [PMID: 31002070]
Pym, A.S.; Diacon, A.H.; Tang, S.J.; Conradie, F.; Danilovits, M.; Chuchottaworn, C.; Vasilyeva, I.; Andries, K.; Bakare, N.; De Marez, T.; Haxaire-Theeuwes, M.; Lounis, N.; Meyvisch, P.; Van Baelen, B.; van Heeswijk, R.P.; Dannemann, B. TMC207-C209 Study Group. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur. Respir. J., 2016, 47(2), 564-574.
[] [PMID: 26647431]
Gao, M.; Gao, J.; Xie, L.; Wu, G.; Chen, W.; Chen, Y.; Pei, Y.; Li, G.; Liu, Y.; Shu, W.; Fan, L.; Wu, Q.; Du, J.; Chen, X.; Tang, P.; Xiong, Y.; Li, M.; Cai, Q.; Jin, L.; Mei, Z.; Pang, Y.; Li, L. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: A multicentre study. Clin. Microbiol. Infect., 2021, 27(4), 597-602.
[] [PMID: 32553880]
Koirala, S.; Borisov, S.; Danila, E.; Mariandyshev, A.; Shrestha, B.; Lukhele, N.; Dalcolmo, M.; Shakya, S.R.; Miliauskas, S.; Kuksa, L.; Manga, S.; Aleksa, A.; Denholm, J.T.; Khadka, H.B.; Skrahina, A.; Diktanas, S.; Ferrarese, M.; Bruchfeld, J.; Koleva, A.; Piubello, A.; Koirala, G.S.; Udwadia, Z.F.; Palmero, D.J.; Munoz-Torrico, M.; Gc, R.; Gualano, G.; Grecu, V.I.; Motta, I.; Papavasileiou, A.; Li, Y.; Hoefsloot, W.; Kunst, H.; Mazza-Stalder, J.; Payen, M.C.; Akkerman, O.W.; Bernal, E.; Manfrin, V.; Matteelli, A.; Mustafa Hamdan, H.; Nieto Marcos, M.; Cadiñanos Loidi, J.; Cebrian Gallardo, J.J.; Duarte, R.; Escobar Salinas, N.; Gomez Rosso, R.; Laniado-Laborín, R.; Martínez Robles, E.; Quirós Fernandez, S.; Rendon, A.; Solovic, I.; Tadolini, M.; Viggiani, P.; Belilovski, E.; Boeree, M.J.; Cai, Q. Davidavičienė E.; Forsman, L.D.; De Los Rios, J.; Drakšienė J.; Duga, A.; Elamin, S.E.; Filippov, A.; Garcia, A.; Gaudiesiute, I.; Gavazova, B.; Gayoso, R.; Gruslys, V.; Jonsson, J.; Khimova, E.; Madonsela, G.; Magis-Escurra, C.; Marchese, V.; Matei, M.; Moschos, C.; Nakčerienė B.; Nicod, L.; Palmieri, F.; Pontarelli, A.; Šmite, A.; Souleymane, M.B.; Vescovo, M.; Zablockis, R.; Zhurkin, D.; Alffenaar, J.W.; Caminero, J.A.; Codecasa, L.R.; García-García, J.M.; Esposito, S.; Saderi, L.; Spanevello, A.; Visca, D.; Tiberi, S.; Pontali, E.; Centis, R.; D’Ambrosio, L.; van den Boom, M.; Sotgiu, G.; Migliori, G.B. Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort. Pulmonology, 2021, 27(5), 403-412.
[] [PMID: 33753021]
Ndjeka, N.; Schnippel, K.; Master, I.; Meintjes, G.; Maartens, G.; Romero, R.; Padanilam, X.; Enwerem, M.; Chotoo, S.; Singh, N.; Hughes, J.; Variava, E.; Ferreira, H.; Te Riele, J.; Ismail, N.; Mohr, E.; Bantubani, N.; Conradie, F. High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen. Eur. Respir. J., 2018, 52(6), 1801528.
[] [PMID: 30361246]
Franke, M.F.; Khan, P.; Hewison, C.; Khan, U.; Huerga, H.; Seung, K.J.; Rich, M.L.; Zarli, K.; Samieva, N.; Oyewusi, L.; Nair, P.; Mudassar, M.; Melikyan, N.; Lenggogeni, P.; Lecca, L.; Kumsa, A.; Khan, M.; Islam, S.; Hussein, K.; Docteur, W.; Chumburidze, N.; Berikova, E.; Atshemyan, H.; Atwood, S.; Alam, M.; Ahmed, S.; Bastard, M.; Mitnick, C.D. Culture conversion in patients treated with bedaquiline and/or delamanid. a prospective multicountry study. Am. J. Respir. Crit. Care Med., 2021, 203(1), 111-119.
[] [PMID: 32706644]
Kang, H.; Jo, K.W.; Jeon, D.; Yim, J.J.; Shim, T.S. Interim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea. Respir. Med., 2020, 167, 105956.
[] [PMID: 32421540]
Dooley, K.E.; Nuermberger, E.L.; Diacon, A.H. Pipeline of drugs for related diseases: Tuberculosis. Curr. Opin. HIV AIDS, 2013, 8(6), 579-585.
[] [PMID: 24100880]
Sharma, S.; Singh, A. Phenothiazines as anti-tubercular agents: Mechanistic insights and clinical implications. Expert Opin. Investig. Drugs, 2011, 20(12), 1665-1676.
[] [PMID: 22014039]
Kristiansen, J.E.; Dastidar, S.G.; Palchoudhuri, S.; Roy, D.S.; Das, S.; Hendricks, O.; Christensen, J.B. Phenothiazines as a solution for multidrug resistant tuberculosis: From the origin to present. Int. Microbiol., 2015, 18(1), 1-12.
[PMID: 26415662]
Rodrigues, L.; Cravo, P.; Viveiros, M. Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: A new strategy to revisit mycobacterial targets and repurpose old drugs. Expert Rev. Anti Infect. Ther., 2020, 18(8), 741-757.
[] [PMID: 32434397]
Gupta, S.; Cohen, K.A.; Winglee, K.; Maiga, M.; Diarra, B.; Bishai, W.R. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2014, 58(1), 574-576.
[] [PMID: 24126586]
Reichlen, M.J.; Leistikow, R.L.; Scobey, M.S.; Born, S.E.M.; Voskuil, M.I. Anaerobic Mycobacterium tuberculosis cell death stems from intracellular acidification mitigated by the DosR regulon. J. Bacteriol., 2017, 199(23), e00320-e17.
[] [PMID: 28874407]
Pasca, M.R.; Guglierame, P.; Arcesi, F.; Bellinzoni, M.; De Rossi, E.; Riccardi, G. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2004, 48(8), 3175-3178.
[] [PMID: 15273144]
Lechartier, B.; Cole, S.T. Mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2015, 59(8), 4457-4463.
[] [PMID: 25987624]
Yew, W.W.; Lee, J. Drug treatment of chronic tuberculous empyema. Chest, 1992, 101(6), 1741-1742.
[] [PMID: 1600813]
Temple, M.E.; Nahata, M.C. Rifapentine: Its role in the treatment of tuberculosis. Ann. Pharmacother., 1999, 33(11), 1203-1210.
[] [PMID: 10573321]
Zheng, C.; Hu, X.; Zhao, L.; Hu, M.; Gao, F. Clinical and pharmacological hallmarks of rifapentine’s use in diabetes patients with active and latent tuberculosis: Do we know enough? Drug Des. Devel. Ther., 2017, 11, 2957-2968.
[] [PMID: 29066867]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy