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Review

Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs

, & ORCID Icon
Pages 741-757 | Received 24 Feb 2020, Accepted 22 Apr 2020, Published online: 20 May 2020

References

  • World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization; 2019.
  • World Health Organization. Global strategy and targets for tuberculosis prevention, care and control after 2015. Geneva: World Health Organization; 2015.
  • Louw GE, Warren RM, Gey van Pittius NC, et al. Balancing act: efflux/influx in mycobacterial drug resistance. Antimicrob Agents Chemother. 2009;53(8):3181–3189.
  • Viveiros M, Martins M, Rodrigues L, et al. Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev Anti Infect Ther. 2012;10(9):983–998.
  • Almeida Da Silva PE, Palomino JC. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. J Antimicrob Chemother. 2011;66(7):1417–1430.
  • Al-Saeedi M, Al-Hajoj S. Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis. Infect Drug Resist. 2017;10:333–342.
  • De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question FEMS. Microbiol Rev. 2006;30(1):36–52.
  • Rodrigues L, Parish T, Balganesh M, et al. Antituberculosis drugs: reducing efflux=increasing activity. Drug Discov Today. 2017;22(3):592–599.
  • Srivastava S, Musuka S, Sherman C, et al. Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol. J Infect Dis. 2010;201(8):1225–1231.
  • Pasipanodya JG, Gumbo T. A new evolutionary and pharmacokinetic–pharmacodynamic scenario for rapid emergence of resistance to single and multiple anti-tuberculosis drugs. Curr Opin Pharmacol. 2011;11(5):457–463. .
  • Machado D, Couto I, Perdigão J, et al. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS One. 2012;7(4):e34538.
  • Schmalstieg AM, Srivastava S, Belkaya S, et al. The antibiotic resistance arrow of time: efflux pump induction is a general first step in the evolution of mycobacterial drug resistance. Antimicrob Agents Chemother. 2012;56(9):4806–4815.
  • Ismail N, Ismail NA, Omar SV, et al. In vitro study of stepwise acquisition of rv0678 and atpE mutations conferring bedaquiline resistance. Antimicrob Agents Chemother. 2019;63(8):pii: e00292-19.
  • Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev. 2006;19(2):382–402.
  • Du D, Wang-Kan X, Neuberger A, et al. Multidrug efflux pumps: structure, function and regulation. Nat Rev Microbiol. 2018;16(9):523–539.
  • Hassan KA, Liu Q, Henderson PJ, et al. Homologs of the Acinetobacter baumannii AceI transporter represent a new family of bacterial multidrug efflux systems. mBio. 2015 Feb 10;6(1):pii: e01982-14.
  • Silva PE, Bigi F, Santangelo MP, et al. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2001;45(3):800–804.
  • Ramón-García S, Martín C, Thompson CJ, et al. Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob Agents Chemother. 2009;53(9):3675–3682.
  • Ramón-García S, Mick V, Dainese E, et al. Functional and genetic characterization of the tap efflux pump in Mycobacterium bovis. BCG Antimicrob Agents Chemother. 2012;56(4):2074–2083.
  • Domenech P, Reed MB, Barry CE 3rd. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect Immun. 2005;73(6):3492–3501.
  • Ma S, Huang Y, Xie F, et al. Transport mechanism of Mycobacterium tuberculosis MmpL/S family proteins and implications in pharmaceutical targeting. Biol Chem. 2020;401(3):331–348.
  • Pasca MR, Guglierame P, De Rossi E, et al. mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob Agents Chemother. 2005;49(11):4775–4777.
  • Tullius MV, Harmston CA, Owens CP, et al. Discovery and characterization of a unique mycobacterial heme acquisition system. Proc Natl Acad Sci USA. 2011;108(12):5051–5056.
  • Grzegorzewicz AE, Pham H, Gundi VA, et al. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol. 2012;8(4):334–341.
  • Varela C, Rittmann D, Singh A, et al. MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol. 2012;19(4):498–506.
  • Owens CP, Chim N, Graves AB, et al. The Mycobacterium tuberculosis secreted protein Rv0203 transfers heme to membrane proteins MmpL3 and MmpL11. J Biol Chem. 2013;288(30):21714–21728.
  • Balganesh M, Kuruppath S, Marcel N, et al. Rv1218c, an ABC transporter of Mycobacterium tuberculosis with implications in drug discovery. Antimicrob Agents Chemother. 2010;54(12):5167–5172.
  • Rodrigues L, Villellas C, Bailo R, et al. Role of the Mmr efflux pump in drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(2):751–757.
  • De Rossi E, Branzoni M, Cantoni R, et al. mmr, a Mycobacterium tuberculosis gene conferring resistance to small cationic dyes and inhibitors. J Bacteriol. 1998;180(22):6068–6071.
  • Ramón-García S, Martín C, Aínsa JA, et al. Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum. J Antimicrob Chemother. 2006;57(2):252–259.
  • Pang Y, Lu J, Wang Y, et al. Study of the rifampin monoresistance mechanism in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(2):893–900.
  • Adams KN, Takaki K, Connolly LE, et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell. 2011;145(1):39–53.
  • Liu J, Shi W, Zhang S, et al. Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide, isoniazid, and streptomycin in M tuberculosis. Front Microbiol. 2019;10:216.
  • Gupta AK, Katoch VM, Chauhan DS, et al. Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microb Drug Resist. 2010;16(1):21–28.
  • Rodrigues L, Machado D, Couto I, et al. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect Genet Evol. 2012;12(4):695–700.
  • Machado D, Pires D, Perdigão J, et al. Ion channel blockers as antimicrobial agents, efflux inhibitors, and enhancers of macrophage killing activity against drug resistant Mycobacterium tuberculosis. PLoS One. 2016;11(2):e0149326.
  • Choudhuri BS, Bhakta S, Barik R, et al. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis. Biochem. 2002;J367(Pt 1):279–285.
  • Zhang Y, Zhang J, Cui P, et al. Identification of novel efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c involved in pyrazinamide resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017;61(8):pii: e00940-17.
  • Pasca MR, Guglierame P, Arcesi F, et al. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2004;48(8):3175–3178.
  • Khosravi AD, Sirous M, Absalan Z, et al. Comparison of drrA and drrB efflux pump genes expression in drug-susceptible and-resistant Mycobacterium tuberculosis strains isolated from tuberculosis patients in Iran. Infect Drug Resist. 2019;12:3437–3444.
  • Danilchanka O, Mailaender C, Niederweis M. Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2008;52(7):2503–2511.
  • Aínsa JA, Blokpoel MC, Otal I, et al. Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacterium fortuitum and Mycobacterium tuberculosis. J Bacteriol. 1998;180(22):5836–5843.
  • Duan W, Li X, Ge Y, et al. Mycobacterium tuberculosis Rv1473 is a novel macrolides ABC Efflux Pump regulated by WhiB7. Future Microbiol. 2019;14:47–59.
  • Ramón-García S, Martín C, De Rossi E, et al. Contribution of the Rv2333c efflux pump (the Stp protein) from Mycobacterium tuberculosis to intrinsic antibiotic resistance in Mycobacterium bovis. BCG J Antimicrob Chemother. 2007;59(3):544–547.
  • Briffotaux J, Huang W, Wang X, et al. MmpS5/MmpL5 as an efflux pump in Mycobacterium species. Tuberculosis (Edinb). 2017;107:13–19.
  • Li B, Ye M, Guo Q, et al. Determination of MIC distribution and mechanisms of decreased susceptibility to bedaquiline among clinical isolates of Mycobacterium abscessus. Antimicrob Agents Chemother. 2018;62(7):pii: e00175–18.
  • Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One. 2014;9(7):e102135.
  • Hartkoorn RC, Uplekar S, Cole ST. Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58(5):2979–2981.
  • Narang A, Garima K, Porwal S, et al. Potential impact of efflux pump genes in mediating rifampicin resistance in clinical isolates of Mycobacterium tuberculosis from India. PLoS One. 2019;14(9):e0223163.
  • Abbate E, Vescovo M, Natiello M, et al. Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother. 2012;67(2):473–477.
  • Udwadia ZF, Sen T, Pinto LM. Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB. Recent Pat Antiinfect Drug Discov. 2011;6(2):88–91.
  • Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol. 2015;6:421.
  • Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3(8):673–683.
  • Kristiansen JE, Dastidar SG, Palchoudhuri S, et al. Phenothiazines as a solution for multidrug resistant tuberculosis: from the origin to present. Int Microbiol. 2015;18(1):112.
  • Rodrigues L, Aínsa JA, Amaral L, et al. Inhibition of drug efflux in mycobacteria with phenothiazines and other putative efflux inhibitors. Recent Pat Antiinfect Drug Discov. 2011;6(2):118–127.
  • Viveiros M, Martins M, Couto I, et al. Molecular tools for rapid identification and novel effective therapy against MDRTB/XDRTB infections. Expert Rev Anti Infect Ther. 2010;8(4):465–480.
  • Amaral L, Viveiros M. Thioridazine: A non-antibiotic drug highly effective, in combination with first line anti-tuberculosis drugs, against any form of antibiotic resistance of Mycobacterium tuberculosis due to its multi-mechanisms of action. Antibiotics (Basel). 2017;6(1):pii: E3.
  • Pieroni M, Machado D, Azzali E, et al. Rational design and synthesis of thioridazine analogues as enhancers of the antituberculosis therapy. J Med Chem. 2015;58(15):5842–5853.
  • Vibe CB, Fenaroli F, Pires D, et al. Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish. Nanotoxicology. 2016;10(6):680–688.
  • Weinstein EA, Yano T, Li LS, et al. Inhibitors of type II NADH: menaquinoneoxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci USA. 2005;102(12):4548–4553.
  • Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307(5707):223–227.
  • Cohen K, Maartens G. A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis. Expert Opin Drug Saf. 2019;18(10):875–882.
  • Speelmans G, Staffhorst RW, De Wolf FA, et al. Verapamil competes with doxorubicin for binding to anionic phospholipids resulting in increased internal concentrations and rates of passive transport of doxorubicin. Biochim Biophys Acta. 1995;1238(2):137–146.
  • Pereira E, Teodori E, Dei S, et al. Reversal of multidrug resistance by verapamil analogues. Biochem Pharmacol. 1995;50(4):451–457.
  • Boxberger KH, Hagenbuch B, Lampe JN. Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake. Drug Metab Dispos. 2014;42(6):990–995.
  • Rodrigues L, Wagner D, Viveiros M, et al. Thioridazine and chlorpromazine inhibition of ethidium bromide efflux in Mycobacterium avium and Mycobacterium smegmatis. J Antimicrob Chemother. 2008;61(5):1076–1082.
  • Rodrigues L, Sampaio D, Couto I, et al. The role of efflux pumps in macrolide resistance in Mycobacterium avium complex. Int J Antimicrob Agents. 2009;34(6):529–533.
  • Singh M, Jadaun GP, Ramdas, et al. Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates. Indian J Med Res. 2011;133:535–540.
  • Louw GE, Warren RM, Gey van Pittius NC, et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. Am J Respir Crit Care Med. 2011;184(2):269–276.
  • Li G, Zhang J, Guo Q, et al. Study of efflux pump gene expression in rifampicin-monoresistant Mycobacterium tuberculosis clinical isolates. J Antibiot (Tokyo). 2015;68(7):431–435.
  • Sun Z, Xu Y, Sun Y, et al. Ofloxacin resistance in Mycobacterium tuberculosis is associated with efflux pump activity independent of resistance pattern and genotype. Microb Drug Resist. 2014;20(6):525–532.
  • Gupta S, Tyagi S, Almeida DV, et al. Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor. Am J Respir Crit Care Med. 2013;188(5):600–607.
  • Gupta S, Cohen KA, Winglee K, et al. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58(1):574–576.
  • Almeida D, Ioerger T, Tyagi S, et al. Mutations in pepQ confer low-level resistance to bedaquiline and clofazimine in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2016;60(8):4590–4599.
  • Adams KN, Szumowski JD, Ramakrishnan RL. Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs. J Infect Dis. 2014;210(3):456–466.
  • Xu J, Tasneen R, Peloquin CA, et al. Verapamil increases the bioavailability and efficacy of bedaquiline but not clofazimine in a murine model of tuberculosis. Antimicrob Agents Chemother. 2017;62(1):pii: e01692–17. .
  • Kotwal P, Magotra A, Dogra A, et al. Assessment of preclinical drug interactions of bedaquiline by a highly sensitive LC-ESI-MS/MS based bioanalytical method. J Chromatogr B Analyt Technol Biomed Life Sci. 2019;1112:48–55.
  • Srikshna G, Gupta S, Dooley KE, et al. Can the addition of verapamil to bedaquiline-containing regimens improve tuberculosis treatment outcomes? A novel approach to optimizing TB treatment. Future Microbiol. 2015;10(8):1257–1260.
  • Ghajavan H, Kargarpour Kamakoli M, Khanipour S, et al. High prevalence of bedaquiline resistance in treatment-naive tuberculosis patients and verapamil effectiveness. Antimicrob Agents Chemother. 2019;63(3):pii: e02530–18.
  • Scani JLR, Camargo AD, Seus VR, et al. Molecular modelling and competitive inhibition of a Mycobacterium tuberculosis multidrug-resistance efflux pump. J Mol Graph Model. 2019;87:98–108.
  • Gupta S, Tyagi S, Bishai WR. Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother. 2015;59(1):673–676.
  • Seral C, Carryn S, Tulkens PM, et al. Influence of P-glycoprotein and MRP efflux pump inhibitors on the intracellular activity of azithromycin and ciprofloxacin in macrophages infected by Listeria monocytogenes or Staphylococcus aureus. J Antimicrob Chemother. 2003;51(5):1167–1173.
  • Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res. 2009;26(9):2039–2054.
  • Ughachukwu P, Unekwe P. Efflux pump-mediated resistance in chemotherapy. Ann Med Health Sci Res. 2012;2(2):191–198.
  • Chen C, Gardete S, Jansen RS, et al. Verapamil targets membrane energetics in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2018;62(5):pii: e02107–17.
  • Pule CM, Sampson SL, Warren RM, et al. Efflux pump inhibitors: targeting mycobacterial efflux systems to enhance TB therapy. J Antimicrob Chemother. 2016;71(1):17–26.
  • Gupta AK, Reddy VP, Lavania M, et al. jefA (Rv2459), a drug efflux gene in Mycobacterium tuberculosis confers resistance to isoniazid & ethambutol. Indian J Med Res. 2010;132:176–188.
  • Colangeli R, Helb D, Sridharan S, et al. The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Mol Microbiol. 2005;55(6):1829–1840.
  • Viveiros M, Portugal I, Bettencourt R, et al. Isoniazid-induced transient high-level resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2002;46(9):2804–2810.
  • Zhang Y, Scorpio A, Nikaido H, et al. Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J Bacteriol. 1999;181(7):2044–2049.
  • Sharma S, Kumar M, Sharma S, et al. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother. 2010;65:1694–1701.
  • Hegeto LA, Caleffi-Ferracioli KR, Nakamura-Vasconcelos SS, et al. In vitro combinatory activity of piperine and anti-tuberculosis drugs in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2018;111:35–40.
  • Jin J, Zhang J-Y, Guo N, et al. Farnesol, a potential efflux pump inhibitor in Mycobacterium smegmatis. Mol Basel Switz. 2010;15:7750–7762.
  • Lechner D, Gibbons S, Bucar F. Plant phenolic compounds as ethidium bromide efflux inhibitors in Mycobacterium smegmatis. J Antimicrob Chemother. 2008;62(2):345–348.
  • Cannalire R, Machado D, Felicetti T, et al. Natural isoflavone biochanin A as a template for the design of new and potent 3-phenylquinolone efflux inhibitors against Mycobacterium avium. Eur J Med Chem. 2017;140:321–330.
  • Balganesh M, Dinesh N, Sharma S, et al. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates Antimicrob. Agents Chemother. 2012;56(5):2643–2651.
  • Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic – a vision for applied use. Biochem Pharmacol. 2006;71(7):910–918.
  • Pagès JM, Amaral L. Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria. Biochim Biophys Acta. 2009;1794(5):826–833.
  • Schuster S, Bohnert JA, Vavra M, et al. Proof of an outer membrane target of the efflux inhibitor phe-arg-ß-naphthylamide from random mutagenesis. Molecules. 2019;24(3):pii: E470.
  • Grossman TH, Shoen CM, Jones SM, et al. The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents. Antimicrob Agents Chemother. 2015;59(3):1534–1541.
  • de Knegt GJ, van der Meijden A, de Vogel CP, et al. Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis in combination with potentiator drugs verapamil, timcodar, colistin and SQ109. Int J Antimicrob Agents. 2017;49(3):302–307.
  • Wescott HH, Zuniga ES, Bajpai A, et al. Identification of enolase as the target of 2-aminothiazoles in Mycobacterium tuberculosis. Front Microbiol. 2018;9:2542.
  • Machado D, Girardini M, Viveiros M, et al. Challenging the drug-likeness dogma for new drug discovery in tuberculosis. Front Microbiol. 2018;9:1367.
  • Machado D, Azzali E, Couto I, et al. Adjuvant therapies against tuberculosis: discovery of a 2-aminothiazole targeting Mycobacterium tuberculosis energetics. Future Microbiol. 2018;13:1383–1402.
  • Black PA, Warren RM, Louw GE, et al. Energy metabolism and drug efflux in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58(5):2491–2503.
  • Bald D, Villellas C, Lu P, et al. Targeting energy metabolism in Mycobacterium tuberculosis, a new paradigm in antimycobacterial drug discovery. mBio. 2017;8(2):pii: e00272–17.
  • Bispo NA, Culleton R, Silva LA, et al. A systematic in silico search for target similarity identifies several approved drugs with potential activity against the Plasmodium falciparum apicoplast. PLoS One. 2013;8(3):e59288.
  • Neves BJ, Braga RC, Bezerra JC, et al. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni. PLoS Negl Trop Dis. 2015;9(1):e3435.
  • Urán Landaburu L, Berenstein AJ, Videla S, et al. TDR Targets 6: driving drug discovery for human pathogens through intensive chemogenomic data integration. Nucleic Acids Res. 2020;48(D1):D992–D1005.
  • Kapopoulou A, Lew JM, Cole ST. The MycoBrowser portal: a comprehensive and manually annotated resource for mycobacterial genomes. Tuberculosis (Edinb). 2011;91(1):8–13.
  • TDR Targets [Internet]. 2020 [cited 2020 Jan 17]. Available from: https://www.tdrtargets.org/
  • Mycobrowser [Internet]. 2020 [cited 2020 Jan 17]. Available from: https://mycobrowser.epfl.ch/
  • Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074–82.
  • Szklarczyk D, Santos A, von Mering C, et al. STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 2016;44(D1):D380–4.
  • Ashkenazy H, Abadi S, Martz E, et al. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucl Acids Res. 2016;44(W1):W344–50.
  • Pubmed [Internet]. 2020 [cited 2020 Jan 17]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/
  • World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis - Interim policy guidance. Geneva: World Health Organization; 2013.
  • Pugazhendhi A, Edison TNJI, Velmurugan BK, et al. Toxicity of doxorubicin (Dox) to different experimental organ systems. Life Sci. 2018;200:26–30.
  • Mordente A, Meucci E, Silvestrini A, et al. New developments in anthracycline-induced cardiotoxicity. Curr Med Chem. 2009;16(13):1656–1672.
  • Weiss RB. The anthracyclines: will we ever find a better doxorubicin. Semin Oncol. 1992;19(6):670–686.
  • Gajadeera C, Willby MJ, Green KD, et al. Antimycobacterial activity of DNA intercalator inhibitors of Mycobacterium tuberculosis primase DnaG. J Antibiot (Tokyo). 2015;68(3):153–157.
  • Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006;319(3):998–1008.
  • Sweeny DJ, Li W, Clough J, et al. Metabolism of fostamatinib, the oral methylene phosphate prodrug of the spleen tyrosine kinase inhibitor R406 in humans: contribution of hepatic and gut bacterial processes to the overall biotransformation. Drug Metab Dispos. 2010;38(7):1166–1176.
  • Baluom M, Grossbard EB, Mant T, et al. Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies. Br J Clin Pharmacol. 2013;76(1):78–88.
  • Rolf MG, Curwen JO, Veldman-Jones M, et al. In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib. Pharmacol Res Perspect. 2015;3(5):e00175.
  • Kanehiro Y, Tomioka H, Pieters J, et al. Identification of novel mycobacterial inhibitors against mycobacterial protein kinase G. Front Microbiol. 2018;J9:1517.
  • Desai A, Mitchison TJ. Tubulin and FtsZ structures: functional and therapeutic implications. Bioessays. 1998;20(7):523–527.
  • Downing KH. Structural basis for the interaction of tubulin with proteins and drugs that affect microtubule dynamics. Annu Rev Cell Dev Biol. 2000;16:89–111.
  • Köhler P, Bachmann R. The effects of the antiparasitic drugs levamisole, thiabendazole, praziquantel, and chloroquine on mitochondrial electron transport in muscle tissue from Ascaris suum. Mol Pharmacol. 1978;14(1):155–163.
  • Slayden RA, Knudson DL, Belisle JT. Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis. Microbiology. 1789–97;152(Pt6):2006.
  • Knudson SE, Awasthi D, Kumar K, et al. A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis. PLoS One. 2014;9(4):e93953.
  • Lopez-Munoz F, Baumeister AA, Hawkins MF, et al. The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth. Actas Esp Psiquiatr. 2012;40(1):34–42.
  • El-Habr EA, Dubois LG, Burel-Vandenbos F, et al. A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. Acta Neuropathol. 2017;133(4):645–660.
  • Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees. Cell Mol Life Sci. 2007;64(16):2090–2103.
  • Bazinet RP, Weis MT, Rapoport SI, et al. Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl). 2006;184(1):122–129.
  • Rao M, Valentini D, Zumla A, et al. Evaluation of the efficacy of valproic acid and suberoylanilide hydroxamic acid (vorinostat) in enhancing the effects of first-line tuberculosis drugs against intracellular Mycobacterium tuberculosis. Int J Infect Dis. 2018;69:78–84.
  • Schiebler M, Brown K, Hegyi K, et al. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med. 2015;7(2):127–139.
  • Blaustein MP, Juhaszova M, Golovina VA. The cellular mechanism of action of cardiotonic steroids: A new hypothesis. Clin Exp Hypertens. 1998;20(5–6):691–703.
  • Wasserstrom JA, Aistrup GL. Digitalis: new actions for an old drug. Am J Physiol Heart Circ Physiol. 2005;289(5):H1781–93.
  • Nguyen AN, Wallace DP, Blanco G. Ouabain binds with high affinity to the Na,K-ATPase in human polycystic kidney cells and induces extracellular signal-regulated kinase activation and cell proliferation. J Am Soc Nephrol. 2007;18(1):46–57.
  • Martins M, Viveiros M, Amaral L. Inhibitors of Ca2+ and K+ transport enhance intracellular killing of M. tuberculosis by non-killing macrophages. In Vivo. 2008;22(1):69–75.
  • Amaral L, Martins M, Viveiros M. Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J Antimicrob Chemother. 2007;59(6):1237–1246.
  • Kaur G, Pandey B, Kumar A, et al. Drug targeted virtual screening and molecular dynamics of LipU protein of Mycobacterium tuberculosis and Mycobacterium leprae. J Biomol Struct Dyn. 2019;37(5):1254–1269.
  • Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–270.
  • Lund SS, Tarnow L, Stehouwer CD, et al. Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. Diabetes Obes Metab. 2007;9(3):394–407.
  • Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–1585.
  • Madiraju AK, Qiu Y, Perry RJ, et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. 2018;24(9):1384–1394.
  • Lee MC, Chiang CY, Lee CH, et al. Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: A nationwide cohort study with validated diagnostic criteria. PLoS One. 2018;13(10):e0205807.
  • Lachmandas E, Eckold C, Böhme J, et al. Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects. J Infect Dis. 2019;220(1):139–150.
  • Rodriguez-Carlos A, Valdez-Miramontes C, Marin-Luevano P, et al. Metformin promotes Mycobacterium tuberculosis killing and increases the production of human ß-defensins in lung epithelial cells and macrophages. Microbes Infect 2020;22(3):111–18.
  • Singhal A, Jie L, Kumar P, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014;6(263):263ra159.
  • Padmapriyadarsini C, Bhavani PK, Natrajan M, et al. Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial. BMJ Open. 2019;9(3):e024363.
  • Rybniker J, Vocat A, Sala C, et al. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015;6:7659.
  • Kovoor PA, Karim SM, Marshall JL. Is levoleucovorin an alternative to racemic leucovorin? A literature review. Clin Colorectal Cancer. 2009;8(4):200–206.
  • Chuang VT, Suno M. Levoleucovorin as replacement for leucovorin in cancer treatment. Ann Pharmacother. 2012;46(10):1349–1357.
  • Mondesir J, Willekens C, Touat M, et al. IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med. 2016;7:171–180.
  • Medeiros BC, Fathi AT, DiNardo CD, et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272–281.
  • Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–731.
  • Puthiamadathil JM, Weinberg BA. Emerging combination therapies for metastatic colorectal cancer - impact of trifluridine/tipiracil. Cancer Manag Res. 2017;9:461–469.
  • Hsu WH, Kuo CH, Wang SS, et al. Acid suppressive agents and risk of Mycobacterium tuberculosis: case-control study. BMC Gastroenterol. 2014;14:91.
  • Cheng KC, Liao KF, Lin CL, et al. Correlation of proton pump inhibitors with pulmonary tuberculosis: a case-control study in Taiwan. Front Pharmacol. 2017;8:481.
  • DrugBank: deslanoside [Internet].; 2020 Jan 3 [cited 2020 Jan 17]. Available from: https://www.drugbank.ca/drugs/DB01078
  • DrugBank: acetyldigitoxin [Internet]. ; 2020 Jan 3 [cited 2020 Jan 17]. Available from: https://www.drugbank.ca/drugs/DB00511
  • DrugBank: ethacrynic acid [Internet]. 2020 Jan 3[cited 2020 Jan 17]. Available from: https://www.drugbank.ca/drugs/DB00903
  • DrugBank: bretylium [Internet]. 2020 Jan 3 [cited 2020 Jan 17]. Available from: https://www.drugbank.ca/drugs/DB01158
  • DrugBank: fomepizole [Internet]. 2020 Jan 3 [cited 2020 Jan 17]. Available from: https://www.drugbank.ca/drugs/DB01213
  • Bovill JG. Inhalation anaesthesia: from diethyl ether to xenon. Handb Exp Pharmacol. 2008;182:121–142.
  • DrugBank: halothane [Internet]. 2020 Jan 3 [cited 2020 Jan 17]. Available from https://www.drugbank.ca/drugs/DB01159
  • DrugBank: isoflurane [Internet]; 2020 Jan 3 [cited 2020 Jan 17]. Available from https://www.drugbank.ca/drugs/DB00753
  • Slade JM. Bacterial growth in isoflurane vapour. Anaesthesia. 1993;48:1053–1054.
  • Martínez-Serrano M, Gerónimo-Pardo M, Martínez-Monsalve A, et al. Antibacterial effect of sevoflurane and isoflurane. Rev Esp Quimioter. 2017;30(2):84–89.
  • A-Rahman A, Pedler S, Bray R, et al. To the editor: effect of anesthetics gases on the growth of Pseudomonas aeruginosa, Haemophilus influenzae, and Staphylococcus aureus. Pediatr Pulmonol. 2002;34(3):226–227.
  • Costa SS, Lopes E, Azzali E, et al. An experimental model for the rapid screening of compounds with potential use against mycobacteria. Assay Drug Dev Technol. 2016;14(9):524–534.
  • Lienhardt C, Lönnroth K, Menzies D, et al. Translational research for tuberculosis elimination: priorities, challenges, and actions. PLoS Med. 2016;13(3):e1001965.
  • Andrade CH, Neves BJ, Melo-Filho CC, et al. In silico chemogenomics drug repositioning strategies for neglected tropical diseases. Curr Med Chem. 2019;26(23):4355–4379.
  • Solnier J, Martin L, Bhakta S, et al. Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species. Molecules. 2020;25(3):E734.
  • Li X, Li P, Ruan C, et al. Mycobacterium tuberculosis Rv0191 is an efflux pump of major facilitator superfamily transporter regulated by Rv1353c. Arch Biochem Biophys. 2019;667:59–66.
  • Khanna A, Raj VS, Tarai B, et al. Emergence and molecular characterization of extensively drug-resistant Mycobacterium tuberculosis clinical isolates from the Delhi Region in India. Antimicrob Agents Chemother. 2010;54(11):4789–4793.
  • De Rossi E, Arrigo P, Bellinzoni M, et al. The multidrug transporters belonging to major facilitator superfamily in Mycobacterium tuberculosis. Mol Med. 2002;8(11):714–724.
  • Li XZ, Zhang L, Nikaido H. Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis. Antimicrob Agents Chemother. 2004;48(7):2415–2423.
  • Doran JL, Pang Y, Mdluli KE, et al. Mycobacterium tuberculosis efpA encodes an efflux protein of the QacA transporter family. Clin Diagn Lab Immunol. 1997;4(1):23–32.
  • Milano A, Pasca MR, Provvedi R, et al. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system. Tuberculosis (Edinb). 2009;89(1):84–90.
  • Chung SY, Sung MK, Kim NH, et al. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch Pharmacal Res. 2005;28(7):823–828.
  • Rao PS, Satelli A, Moridani M, et al. Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms. Int J Cancer. 2012;130(11):2703–2714.
  • Suzuki K, Tsuyuguchi K, Matsumoto H, et al. Effect of proton pump inhibitor alone or in combination with clarithromycin on mycobacterial growth in human alveolar macrophages. FEMS Microbiol Lett. 2000;182(1):69–72.