Skip to content
2000
Volume 16, Issue 3
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702

Abstract

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.

Loading

Article metrics loading...

/content/journals/cmp/10.2174/1874467215666220421130707
2023-06-01
2025-05-02
Loading full text...

Full text loading...

References

  1. SaravanabavanN. ShanmuganathanP. KumarappanM. Bedaquiline: A Mini Review.Ann SBV.2020812410.5005/jp‑journals‑10085‑8101
    [Google Scholar]
  2. CorbettE.L. WattC.J. WalkerN. MaherD. WilliamsB.G. RaviglioneM.C. DyeC. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic.Arch. Intern. Med.200316391009102110.1001/archinte.163.9.1009 12742798
    [Google Scholar]
  3. Rodriguez-TakeuchiS.Y. RenjifoM.E. MedinaF.J. Extrapulmonary tuberculosis: Pathophysiology and imaging findings.Radiographics20193972023203710.1148/rg.2019190109 31697616
    [Google Scholar]
  4. LangeC. ChesovD. HeyckendorfJ. LeungC.C. UdwadiaZ. DhedaK. Drug-resistant tuberculosis: An update on disease burden, diagnosis and treatment.Respirology201823765667310.1111/resp.13304 29641838
    [Google Scholar]
  5. NguyenL. Antibiotic resistance mechanisms in M. tuberculosis: An update.Arch. Toxicol.20169071585160410.1007/s00204‑016‑1727‑6 27161440
    [Google Scholar]
  6. SandhuG.K. Tuberculosis: Current situation, challenges and overview of its control programs in India.J. Glob. Infect. Dis.20113214315010.4103/0974‑777X.81691 21731301
    [Google Scholar]
  7. WHO G.Global tuberculosis report 2020.Glob. Tuberc. Rep.2020
    [Google Scholar]
  8. ChakayaJ. KhanM. NtoumiF. AklilluE. FatimaR. MwabaP. KapataN. MfinangaS. HasnainS.E. KatotoP.D. BulabulaA.N. Global tuberculosis report 2020-reflections on the global tb burden, treatment and prevention efforts.IJID2020
    [Google Scholar]
  9. BasarabaR.J. Experimental tuberculosis: The role of comparative pathology in the discovery of improved tuberculosis treatment strategies.Tuberculosis (Edinb.)200888Suppl. 1S35S4710.1016/S1472‑9792(08)70035‑0 18762152
    [Google Scholar]
  10. WongE.B. CohenK.A. BishaiW.R. Rising to the challenge: New therapies for tuberculosis.Trends Microbiol.201321949350110.1016/j.tim.2013.05.002 23764389
    [Google Scholar]
  11. AndriesK. VerhasseltP. GuillemontJ. GöhlmannH.W. NeefsJ.M. WinklerH. Van GestelJ. TimmermanP. ZhuM. LeeE. WilliamsP. de ChaffoyD. HuitricE. HoffnerS. CambauE. Truffot-PernotC. LounisN. JarlierV. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.Science2005307570722322710.1126/science.1106753 15591164
    [Google Scholar]
  12. LakshmananM. XavierA.S. Bedaquiline - The first ATP synthase inhibitor against multi drug resistant tuberculosis.J. Young Pharm.20135411211510.1016/j.jyp.2013.12.002 24563587
    [Google Scholar]
  13. KoulA. DendougaN. VergauwenK. MolenberghsB. VranckxL. WillebrordsR. RisticZ. LillH. DorangeI. GuillemontJ. BaldD. AndriesK. Diarylquinolines target subunit c of mycobacterial ATP synthase.Nat. Chem. Biol.20073632332410.1038/nchembio884 17496888
    [Google Scholar]
  14. 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.201357116817610.1128/AAC.01039‑12 23089752
    [Google Scholar]
  15. SarathyJ.P. GruberG. DickT. Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline.Antibiotics (Basel)20198426110.3390/antibiotics8040261 31835707
    [Google Scholar]
  16. SinghH. NattN.K. GarewalN. PugazhenthanT. Bedaquiline: A new weapon against MDR and XDR-TB.Int. J. Basic Clin. Pharmacol.2013229610210.5455/2319‑2003.ijbcp20130301
    [Google Scholar]
  17. HaagsmaA.C. PodascaI. KoulA. AndriesK. GuillemontJ. LillH. BaldD. Probing the interaction of the diarylquinoline TMC207 with its target mycobacterial ATP synthase.PLoS One201168e2357510.1371/journal.pone.0023575 21858172
    [Google Scholar]
  18. DooleyK.E. ParkJ.G. SwindellsS. AllenR. HaasD.W. CramerY. AweekaF. WigginsI. GuptaA. LizakP. QasbaS. 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.1999595455
    [Google Scholar]
  19. DiaconA.H. DonaldP.R. PymA. GrobuschM. PatientiaR.F. MahanyeleR. BantubaniN. NarasimoolooR. De MarezT. van HeeswijkR. LounisN. MeyvischP. AndriesK. McNeeleyD.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.20125663271327610.1128/AAC.06126‑11 22391540
    [Google Scholar]
  20. MesensN. SteemansM. HansenE. VerheyenG.R. Van GoethemF. Van GompelJ. Screening for phospholipidosis induced by central nervous drugs: Comparing the predictivity of an in-vitro assay to high throughput in silico assays.Toxicol. In Vitro20102451417142510.1016/j.tiv.2010.04.007 20430096
    [Google Scholar]
  21. AkkermanO.W. OdishO.F. BolhuisM.S. de LangeW.C. KremerH.P. LuijckxG.J. van der WerfT.S. AlffenaarJ.W. Pharmacokinetics of bedaquiline in cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis.Clin. Infect. Dis.2016624523524 26534926
    [Google Scholar]
  22. KwonY.S. KohW.J. Synthetic investigational new drugs for the treatment of tuberculosis.Expert Opin. Investig. Drugs201625218319310.1517/13543784.2016.1121993 26576631
    [Google Scholar]
  23. De MatteisL. JaryD. LucíaA. García-EmbidS. Serrano-SevillaI. PérezD. AinsaJ.A. NavarroF.P. De la FuenteJ.M. New active formulations against M. tuberculosis: Bedaquiline encapsulation in lipid nanoparticles and chitosan nanocapsules.Chem. Eng. J.201834018119110.1016/j.cej.2017.12.110
    [Google Scholar]
  24. RawalT. PatelS. ButaniS. Chitosan nanoparticles as a promising approach for pulmonary delivery of bedaquiline.Eur. J. Pharm. Sci.201812427328710.1016/j.ejps.2018.08.038 30176365
    [Google Scholar]
  25. PamreddyA. BaijnathS. NaickerT. NtshangaseS. MdandaS. LubanyanaH. KrugerH.G. GovenderT. Bedaquiline has potential for targeting tuberculosis reservoirs in the central nervous system.RSC Advances2018822119021190710.1039/C8RA00984H
    [Google Scholar]
  26. KaushikA. AmmermanN.C. TyagiS. SainiV. VervoortI. Lachau-DurandS. NuermbergerE. AndriesK. Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection.Antimicrob. Agents Chemother.2019634e00007e0001910.1128/AAC.00007‑19 30745396
    [Google Scholar]
  27. PohW. Ab RahmanN. OstrovskiY. SznitmanJ. PetheK. LooS.C.J. Active pulmonary targeting against tuberculosis (TB) via triple-encapsulation of Q203, bedaquiline and superparamagnetic iron oxides (SPIOs) in nanoparticle aggregates.Drug Deliv.20192611039104810.1080/10717544.2019.1676841 31691600
    [Google Scholar]
  28. HemelryckS.V. DewulfJ. NiekusH. van HeerdenM. IngelseB. HolmR. MannaertE. LangguthP. In-vitro evaluation of poloxamer in situ forming gels for bedaquiline fumarate salt and pharmacokinetics following intramuscular injection in rats.Int. J. Pharm. X2019110001610.1016/j.ijpx.2019.100016 31517281
    [Google Scholar]
  29. Soria-CarreraH. LucíaA. De MatteisL. AínsaJ.A. de la FuenteJ.M. Martín-RapúnR. Polypeptidic micelles stabilized with sodium alginate enhance the activity of encapsulated bedaquiline.Macromol. Biosci.2019194e180039710.1002/mabi.201800397 30645022
    [Google Scholar]
  30. MominM.A.M. RangnekarB. SinhaS. CheungC.Y. CookG.M. DasS.C. Inhalable dry powder of bedaquiline for pulmonary tuberculosis: In-vitro physicochemical characterization, antimicrobial activity and safety studies.Pharmaceutics2019111050210.3390/pharmaceutics11100502 31581469
    [Google Scholar]
  31. DiaconA.H. PymA. GrobuschM.P. de los RiosJ.M. GotuzzoE. VasilyevaI. LeimaneV. AndriesK. BakareN. De MarezT. Haxaire-TheeuwesM. LounisN. MeyvischP. De PaepeE. van HeeswijkR.P. DannemannB. TMC207-C208 Study GroupMultidrug-resistant tuberculosis and culture conversion with bedaquiline.N. Engl. J. Med.2014371872373210.1056/NEJMoa1313865 25140958
    [Google Scholar]
  32. BorisovS.E. DhedaK. EnweremM. Romero LeyetR. D’AmbrosioL. CentisR. SotgiuG. TiberiS. AlffenaarJ.W. MaryandyshevA. BelilovskiE. GanatraS. SkrahinaA. AkkermanO. AleksaA. AmaleR. ArtsukevichJ. BruchfeldJ. CamineroJ.A. Carpena MartinezI. CodecasaL. DalcolmoM. DenholmJ. DouglasP. DuarteR. EsmailA. FadulM. FilippovA. Davies ForsmanL. GagaM. Garcia-FuertesJ.A. García-GarcíaJ.M. GualanoG. JonssonJ. KunstH. LauJ.S. Lazaro MastrapaB. Teran TroyaJ.L. MangaS. ManikaK. González MontanerP. MullerpattanJ. OelofseS. OrtelliM. PalmeroD.J. PalmieriF. PapaliaA. PapavasileiouA. PayenM.C. PontaliE. Robalo CordeiroC. SaderiL. SadutshangT.D. SanukevichT. SolodovnikovaV. SpanevelloA. TopgyalS. ToscaniniF. TramontanaA.R. UdwadiaZ.F. ViggianiP. WhiteV. ZumlaA. MiglioriG.B. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study.Eur. Respir. J.2017495170038710.1183/13993003.00387‑2017 28529205
    [Google Scholar]
  33. GuglielmettiL. JaspardM. Le DûD. LachâtreM. Marigot-OuttandyD. BernardC. VezirisN. RobertJ. YazdanpanahY. CaumesE. Fréchet-JachymM. French MDR-TB Management Group French MDR-TB Management Group.Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis.Eur. Respir. J.2017493160179910.1183/13993003.01799‑2016 28182570
    [Google Scholar]
  34. MbuagbawL. GuglielmettiL. HewisonC. BakareN. BastardM. CaumesE. Fréchet-JachymM. RobertJ. VezirisN. KhachatryanN. KotrikadzeT. HayrapetyanA. AvalianiZ. SchünemannH.J. LienhardtC. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis.Emerg. Infect. Dis.201925593694310.3201/eid2505.181823 31002070
    [Google Scholar]
  35. PymA.S. DiaconA.H. TangS.J. ConradieF. DanilovitsM. ChuchottawornC. VasilyevaI. AndriesK. BakareN. De MarezT. Haxaire-TheeuwesM. LounisN. MeyvischP. Van BaelenB. van HeeswijkR.P. DannemannB. TMC207-C209 Study GroupBedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis.Eur. Respir. J.201647256457410.1183/13993003.00724‑2015 26647431
    [Google Scholar]
  36. GaoM. GaoJ. XieL. WuG. ChenW. ChenY. PeiY. LiG. LiuY. ShuW. FanL. WuQ. DuJ. ChenX. TangP. XiongY. LiM. CaiQ. JinL. MeiZ. PangY. LiL. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: A multicentre study.Clin. Microbiol. Infect.202127459760210.1016/j.cmi.2020.06.004 32553880
    [Google Scholar]
  37. KoiralaS. BorisovS. DanilaE. MariandyshevA. ShresthaB. LukheleN. DalcolmoM. ShakyaS.R. MiliauskasS. KuksaL. MangaS. AleksaA. DenholmJ.T. KhadkaH.B. SkrahinaA. DiktanasS. FerrareseM. BruchfeldJ. KolevaA. PiubelloA. KoiralaG.S. UdwadiaZ.F. PalmeroD.J. Munoz-TorricoM. GcR. GualanoG. GrecuV.I. MottaI. PapavasileiouA. LiY. HoefslootW. KunstH. Mazza-StalderJ. PayenM.C. AkkermanO.W. BernalE. ManfrinV. MatteelliA. Mustafa HamdanH. Nieto MarcosM. Cadiñanos LoidiJ. Cebrian GallardoJ.J. DuarteR. Escobar SalinasN. Gomez RossoR. Laniado-LaborínR. Martínez RoblesE. Quirós FernandezS. RendonA. SolovicI. TadoliniM. ViggianiP. BelilovskiE. BoereeM.J. CaiQ. 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.Pulmonology202127540341210.1016/j.pulmoe.2021.02.006 33753021
    [Google Scholar]
  38. NdjekaN. SchnippelK. MasterI. MeintjesG. MaartensG. RomeroR. PadanilamX. EnweremM. ChotooS. SinghN. HughesJ. VariavaE. FerreiraH. Te RieleJ. IsmailN. MohrE. BantubaniN. ConradieF. High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.Eur. Respir. J.2018526180152810.1183/13993003.01528‑2018 30361246
    [Google Scholar]
  39. FrankeM.F. KhanP. HewisonC. KhanU. HuergaH. SeungK.J. RichM.L. ZarliK. SamievaN. OyewusiL. NairP. MudassarM. MelikyanN. LenggogeniP. LeccaL. KumsaA. KhanM. IslamS. HusseinK. DocteurW. ChumburidzeN. BerikovaE. AtshemyanH. AtwoodS. AlamM. AhmedS. BastardM. MitnickC.D. Culture conversion in patients treated with bedaquiline and/or delamanid. a prospective multicountry study.Am. J. Respir. Crit. Care Med.2021203111111910.1164/rccm.202001‑0135OC 32706644
    [Google Scholar]
  40. KangH. JoK.W. JeonD. YimJ.J. ShimT.S. Interim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea.Respir. Med.202016710595610.1016/j.rmed.2020.105956 32421540
    [Google Scholar]
  41. DooleyK.E. NuermbergerE.L. DiaconA.H. Pipeline of drugs for related diseases: Tuberculosis.Curr. Opin. HIV AIDS20138657958510.1097/COH.0000000000000009 24100880
    [Google Scholar]
  42. SharmaS. SinghA. Phenothiazines as anti-tubercular agents: Mechanistic insights and clinical implications.Expert Opin. Investig. Drugs201120121665167610.1517/13543784.2011.628657 22014039
    [Google Scholar]
  43. KristiansenJ.E. DastidarS.G. PalchoudhuriS. RoyD.S. DasS. HendricksO. ChristensenJ.B. Phenothiazines as a solution for multidrug resistant tuberculosis: From the origin to present.Int. Microbiol.2015181112 26415662
    [Google Scholar]
  44. RodriguesL. CravoP. ViveirosM. 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.202018874175710.1080/14787210.2020.1760845 32434397
    [Google Scholar]
  45. GuptaS. CohenK.A. WingleeK. MaigaM. DiarraB. BishaiW.R. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis.Antimicrob. Agents Chemother.201458157457610.1128/AAC.01462‑13 24126586
    [Google Scholar]
  46. ReichlenM.J. LeistikowR.L. ScobeyM.S. BornS.E.M. VoskuilM.I. Anaerobic Mycobacterium tuberculosis cell death stems from intracellular acidification mitigated by the DosR regulon.J. Bacteriol.201719923e00320e1710.1128/JB.00320‑17 28874407
    [Google Scholar]
  47. PascaM.R. GuglierameP. ArcesiF. BellinzoniM. De RossiE. RiccardiG. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis.Antimicrob. Agents Chemother.20044883175317810.1128/AAC.48.8.3175‑3178.2004 15273144
    [Google Scholar]
  48. LechartierB. ColeS.T. Mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis.Antimicrob. Agents Chemother.20155984457446310.1128/AAC.00395‑15 25987624
    [Google Scholar]
  49. YewW.W. LeeJ. Drug treatment of chronic tuberculous empyema.Chest199210161741174210.1378/chest.101.6.1741‑b 1600813
    [Google Scholar]
  50. TempleM.E. NahataM.C. Rifapentine: Its role in the treatment of tuberculosis.Ann. Pharmacother.199933111203121010.1345/aph.18450 10573321
    [Google Scholar]
  51. ZhengC. HuX. ZhaoL. HuM. GaoF. Clinical and pharmacological hallmarks of rifapentine’s use in diabetes patients with active and latent tuberculosis: Do we know enough?Drug Des. Devel. Ther.2017112957296810.2147/DDDT.S146506 29066867
    [Google Scholar]
/content/journals/cmp/10.2174/1874467215666220421130707
Loading
/content/journals/cmp/10.2174/1874467215666220421130707
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test