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TMC207 becomes bedaquiline, a new anti-TB drug

    Juan Carlos Palomino

    * Author for correspondence

    Laboratory of Microbiology, Department of Biochemistry & Microbiology, Faculty of Sciences, Ghent University, 9000, Ghent, Belgium.

    &
    Anandi Martin

    Laboratory of Microbiology, Department of Biochemistry & Microbiology, Faculty of Sciences, Ghent University, 9000, Ghent, Belgium

    Published Online:https://doi.org/10.2217/fmb.13.85

    TB still represents a serious public health problem. The latest reports estimate an incidence of 8.7 million cases in 2011 and 1.4 million deaths. Drug resistance contributed an estimated 630,000 cases of multidrug-resistant TB, making control of the disease harder. Recent reports show cases of TB that were almost resistant to all available antibiotics. Therefore, there is an urgent need to develop new anti-TB drugs with the potential of reducing the current length of treatment. Bedaquiline, formerly TMC207, is a new diarylquinoline antibiotic with specific activity against Mycobacterium tuberculosis and several nontuberculous mycobacteria. It acts by inhibiting ATP synthase, interfering with the energy generation needed by the bacterial cell. Based on clinical evaluations for safety, tolerability and efficacy, bedaquiline has recently received accelerated approval for the treatment of pulmonary multidrug-resistant TB in adults. This article will review the main aspects related to the chemistry, microbiology, pharmacology, efficacy and tolerability of bedaquiline.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Almeida da Silva PE, Palomino JC. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. J. Antimicrob. Chemother.66(7),1417–1430 (2011).▪ Presents a recent update on the molecular mechanisms of drug resistance in TB.
    • Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin. Infect. Dis.54(4),579–581 (2012).
    • Migliori GB, Centis R, D’Ambrosio L et al. Totally drug-resistant and extremely drug-resistant tuberculosis: the same disease? Clin. Infect. Dis.54(9),1379–1380 (2012).
    • WHO. Treatment of Tuberculosis Guidelines (4th Edition). WHO, Geneva, Switzerland (2009).
    • Lienhardt C, Vernon A, Raviglione MC. New drugs and new regimens for the treatment of tuberculosis: review of the drug development pipeline and implications for national programmes. Curr. Opin. Pulm. Med.16(3),186–193 (2010).
    • Palomino JC, Martin A. Is repositioning of drugs a viable alternative in the treatment of tuberculosis? J. Antimicrob. Chemother.68(2),275–283 (2013).
    • Grosset JH, Singer TG, Bishai WR. New drugs for the treatment of tuberculosis: hope and reality. Int. J. Tuberc. Lung Dis.16(8),1005–1014 (2012).▪▪ Concise and up-to-date review of the new drugs currently in development for the treatment of TB.
    • Matsumoto M, Hashizume H, Tomishige T et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med.3(11),e466 (2006).
    • Diacon AH, Dawson R, Hanekom M et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int. J. Tuberc. Lung Dis.15(7),949–954 (2011).
    • 10  Gler MT, Skripconoka V, Sanchez-Garavito E et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N. Engl. J. Med.366(23),2151–2160 (2012).
    • 11  Stover CK, Warrener P, VanDevanter DR et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature405(6789),962–966 (2000).
    • 12  Diacon AH, Dawson R, Hanekom M et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob. Agents Chemother.53(8),3402–3407 (2010).
    • 13  Diacon AH, Dawson R, du Bois J et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob. Agents Chemother.56(6),3027–3231 (2012).
    • 14  Villemagne B, Crauste C, Flipo M, Baulard AR, Déprez B, Willand N. Tuberculosis: the drug development pipeline at a glance. Eur. J. Med. Chem.51,1–16 (2012).▪ Describes the current TB drug development pipeline.
    • 15  Cheepsattayakorn A, Cheepsattayakorn R. Novel compounds and drugs and recent patents in treating multidrug-resistant and extensively drug-resistant tuberculosis. Recent Pat. Antiinfect. Drug Discov.7(2),141–156 (2012).
    • 16  Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob. Agents Chemother.51(11),4202–4204 (2007).
    • 17  Andries K, Verhasselt P, Guillemont J et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science307(5707),223–227 (2005).▪▪ Key publication describing the discovery and initial evaluation of bedaquiline against Mycobacterium tuberculosis.
    • 18  Lenaerts AJ, Hoff D, Aly S et al. Location of persisting Mycobacteria in a guinea pig model of tuberculosis revealed by r207910. Antimicrob. Agents Chemother.51(9),3338–3345 (2007).
    • 19  Lounis N, Guillemont J, Veziris N, Koul A, Jarlier V, Andries K. R207910 (TMC207): un nouvel antibiotique pour le traitement de la tuberculose. Med. Mal. Infect.40(7),383–390 (2010).
    • 20  Gaurrand S, Desjardins S, Meyer C et al. Conformational analysis of r207910, a new drug candidate for the treatment of tuberculosis, by a combined NMR and molecular modeling approach. Chem. Biol. Drug Des.68(2),77–84 (2006).
    • 21  Petit S, Coquerel G, Meyer C, Guillemont J. Absolute configuration and structural features of R207910, a novel antituberculosis agent. J. Mol. Struct.837(1–3),252–256 (2007).
    • 22  Koul A, Dendouga N, Vergauwen K et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat. Chem. Biol.3(6),323–324 (2007).
    • 23  Haagsma AC, Abdillahi-Ibrahim R, Wagner MJ et al. Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue. Antimicrob. Agents Chemother.53(3),1290–1292 (2009).
    • 24  Petrella S, Cambau E, Chauffour A et al. Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob. Agents Chemother.50(8),2853–2856 (2006).
    • 25  Segala E, Sougakoff W, Nevejans-Chauffour A, Jarlier V, Petrella S. New mutations in the mycobacterial ATP synthase: new insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-ring structure. Antimicrob. Agents Chemother.56(5),2326–2634 (2012).
    • 26  Huitric E, Verhasselt P, Koul A, Andries K, Hoffner S, Andersson DI. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob. Agents Chemother.54(3),1022–1028 (2010).
    • 27  Ji B, Lefrançois S, Robert J, Chauffour A, Truffot C, Jarlier V. In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against Mycobacterium ulcerans. Antimicrob. Agents Chemother.50(6),1921–1926 (2006).
    • 28  Lechartier B, Hartkoorn RC, Cole ST. In vitro combination studies of Benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother.56(11),5790–5793 (2012).
    • 29  Reddy VM, Einck L, Andries K, Nacy CA. In vitro interactions between new antitubercular drug candidates SQ109 and TMC207. Antimicrob. Agents Chemother.54(7),2840–2846 (2010).
    • 30  Rustomjee R, Diacon AH, Allen J et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob. Agents Chemother.52(8),2831–2835 (2008).▪ Describes the bactericidal activity of bedaquiline in TB patients.
    • 31  Diacon AH, Dawson R, Von Groote-Bidlingmaier FT et al. A randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. Antimicrob. Agents Chemother.57(5),2199–2203 (2013).
    • 32  Diacon AH, Pym A, Grobusch M et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N. Engl. J. Med.360(23),2397–2405 (2009).▪▪ Key publication describing the results of a Phase II clinical trial of bedaquiline.
    • 33  Diacon AH, Donald PR, Pym A et al. 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.56(6),3271–3276 (2012).
    • 34  Roehr B. FDA approves rifapentine for the treatment of pulmonary tuberculosis. J. Int. Assoc. Physicians AIDS Care4(8),19–25 (1998).
    • 35  Dorman SE, Goldberg S, Stout JE et al. Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. J. Infect. Dis.206(7),1030–1040 (2012).
    • 36  Lounis N, Gevers T, Van Den Berg J, Andries K. Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob. Agents Chemother.52(10),3568–3572 (2008).
    • 37  Dooley KE, Park JG, Swindells S et al. 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.59(5),455–462 (2012).
    • 38  Diacon AH, Dawson R, von Groote-Bidlingmaier F et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet380(9846),986–993 (2012).▪ Describes the results of the first bactericidal activity study that tested new drug combinations for TB.
    • 39  Shang S, Shanley CA, Caraway ML et al. Activities of TMC207, rifampin, and pyrazinamide against Mycobacterium tuberculosis infection in guinea pigs. Antimicrob. Agents Chemother.55(1),124–131 (2011).
    • 101  WHO. Global tuberculosis report 2012. www.who.int/tb/publications/global_report/gtbr12_main.pdf
    • 102  A study to evaluate the efficacy and safety of TMC207 in patients with pulmonary infection with multi-drug resistant Mycobacterium tuberculosis. www.clinicaltrials.gov/ct2/show/NCT01600963
    • 103  Anti-Infective Drugs Advisory Committee Meeting Briefing Document. TMC207 (bedaquiline). www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329260.pdf
    • 104  ClinicalTrials.gov. http://clinicaltrials.gov
    • 105  TMC207-TiDP13-C117: interaction study in human immunodeficiency virus-type 1 (HIV-1) infected patients with nevirapine (NVP). www.clinicaltrials.gov/ct2/show/NCT00910806
    • 106  Treatment of patients with MDR-TB. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329260.pdf
    • 107  TMC207-TiDP13-C110: interaction study with lopinavir/ritonavir in healthy volunteer. www.clinicaltrials.gov/ct2/show/NCT00828529
    • 108  Summary Minutes of the Anti-Infective Drugs Advisory Committee, 3 June 2009. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM183845.pdf