Combating Multi-drug Resistant Mycobacterium Species by Efflux Pump Inhibitors: Contemporary Trends

Abstract

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) complex (MTBC), which includes M.tb as one of the causative bacteria. In contrast, non-tuberculous mycobacteria (NTM) refers to Mycobacterium spp. that do not cause TB or leprosy (MTBC spp., M. leprae, and M. lepromatosis). Mycobacterium spp. are responsible for the deadliest infections and remain a significant challenge in diagnosis and treatment. Mycobacterium spp. have developed multiple complementary mechanisms to defend against antibiotics. Specifically, the mechanisms include modifying the drug target sites, enzymatically inactivating the drugs, and lowering intracellular antibiotic concentrations by overexpressing efflux pumps. These adaptations contribute to the emergence of multi-drug resistant pathogens. This review provides an overview of antibiotic resistance inMycobacterium spp. with a focus on several key factors, such as enzyme-mediated antibiotic deactivation, gene expression, biofilm formation, and the role of efflux pumps. A critical objective of this review includes Mycobacterium efflux pumps, the significant role in antibiotic resistance, and compounds that act against these efflux pumps.

Keywords

ABC superfamily / efflux pump / MFS superfamily / Mycobacterium tuberculosis / non-tuberculous mycobacteria / RND superfamily / SMR superfamily / tuberculosis

References

[1] Pushkaran AC, Biswas R, Mohan CG. Impact of target-based drug design in anti-bacterial drug discovery for the treatment of tuberculosis. In: Mohan C, editor. Structural bioinformatics: applications in preclinical drug discovery process. Challenges and advances in computational chemistry and physics. Springer, Cham.; 2019. pp. 307-46.

[2] Feehan KT, Gilroy DW. Is resolution the end of inflammation? Trends Mol Med 2019; 25(3): 198-214. [PMID: 30795972 DOI: 10.1016/j.molmed.2019.01.006]

[3] Bagcchi S. WHO’s global tuberculosis report 2022. Lancet Microbe 2023; 4(1): e20. [PMID: 36521512 DOI: 10.1016/S2666-5247(22)00359-7]

[4] Momin MAM, Tucker IG, Das SC. High dose dry powder inhalers to overcome the challenges of tuberculosis treatment. Int J Pharm 2018; 550(1-2): 398-417. [PMID: 30179703 DOI: 10.1016/j.ijpharm.2018.08.061]

[5] Reuter A, Hughes J, Furin J. Challenges and controversies in childhood tuberculosis. Lancet 2019; 394(10202): 967-78. [PMID: 31526740 DOI: 10.1016/S0140-6736(19)32045-8]

[6] Torrey HL, Keren I, Via LE, Lee JS, Lewis K. High persister mutants in Mycobacterium tuberculosis . PLoS One 2016; 11(5): e0155127. [PMID: 27176494 DOI: 10.1371/journal.pone.0155127]

[7] Fedrizzi T, Meehan CJ, Grottola A, Giacobazzi E, Fregni Serpini G, et al. Genomic characterization of nontuberculous mycobacteria. Sci Rep 2017; 7(1): 45258.

[8] Falkinham JO. Current epidemiologic trends of the nontuberculous mycobacteria (NTM). Curr Environ Health Rep 2016; 3(2): 161-7. [PMID: 27020801 DOI: 10.1007/s40572-016-0086-z]

[9] Falkinham JO. Ecology of nontuberculous mycobacteria. Microorganisms 2021; 9(11): 1-10. [PMID: 34835388 DOI: 10.3390/microorganisms9112262]

[10] Porvaznik I, Solovič I, Mokrý J. Non-tuberculous mycobacteria: classification, diagnostics, and therapy. Adv Exp Med Biol 2016; 944: 19-25. [PMID: 27826888 DOI: 10.1007/5584_2016_45]

[11] Poonam, Yennamalli RM, Bisht GS, Shrivastava R. Ribosomal maturation factor (RimP) is essential for survival of nontuberculous mycobacteria Mycobacterium fortuitum under in vitro acidic stress conditions. 3 Biotech 2019; 9(4): 127. [PMID: 30863706 DOI: 10.1007/s13205-019-1659-y]

[12] Swain A, Gnanasekar P, Prava J, Rajeev AC, Kesarwani P, et al. A comparative genomics approach for shortlisting broad-spectrum drug targets in nontuberculous mycobacteria. Microb Drug Resist 2021; 27(2): 212-26. [PMID: 32936741 DOI: 10.1089/mdr.2020.0161]

[13] Huang HL, Lu PL, Lee CH, Chong IW. Treatment of pulmonary disease caused by Mycobacterium kansasii . J Formos Med Assoc 2020; 119: S51-7. [PMID: 32505588 DOI: 10.1016/j.jfma.2020.05.018]

[14] Mogami R, Goldenberg T, de Marca PG, Mello FC, Lopes AJ. Pulmonary infection caused by Mycobacterium kansasii: findings on computed tomography of the chest. Radiol Bras 2016; 49(4): 209-13. [PMID: 27777472 DOI: 10.1590/0100-3984.2015.0078]

[15] Coolen-Allou N, Touron T, Belmonte O, Gazaille V, Andre M, et al. Clinical, radiological, and microbiological characteristics of Mycobacterium simiae infection in 97 patients. Antimicrob Agents Chemother 2018; 62(7): e00395-18. [PMID: 9760130 DOI: 10.1128/AAC.00395-18]

[16] Sette CS, Wachholz PA, Masuda PY, da Costa Figueira RBF, de Oliveira Mattar FR, et al. Mycobacterium marinum infection: a case report. J Venom Anim Toxins Incl Trop Dis 2015; 21(1): 7. [PMID: 25806076 DOI: 10.1186/s40409-015-0008-9]

[17] Johnson MG, Stout JE. Twenty-eight cases of Mycobacterium marinum infection: retrospective case series and literature review. Infection 2015; 43(6): 655-62. [PMID: 25869820 DOI: 10.1007/s15010-015-0776-8]

[18] Chen Y, Jiang J, Jiang H, Chen J, Wang X, et al. Mycobacterium gordonae in patient with facial ulcers, nosebleeds, and positive T-SPOT.TB test, China. Emerg Infect Dis 2017; 23(7): 1204-6. [PMID: 28628445 DOI: 10.3201/eid2307.162033]

[19] Utsugi H, Usui Y, Nishihara F, Kanazawa M, Nagata M. Mycobacterium gordonae-induced humidifier lung. BMC Pulm Med 2015; 15(1): 108. [PMID: 26420433 DOI: 10.1186/s12890-015-0107-y]

[20] Lotfi H, Sankian M, Meshkat Z, Khalifeh Soltani A, Aryan E. Mycobacterium szulgai pulmonary infection in a vitamin D-deficient patient: a case report. Clin Case Rep 2021; 9(3): 1146- 9. [PMID: 33768798 DOI: 10.1002/ccr3.3692]

[21] Wilson JW, Jagtiani AC, Wengenack NL. Mycobacterium scrofulaceum disease: experience from a tertiary medical centre and review of the literature. Infect Dis 2019; 51(8): 602-9. [PMID: 31264491 DOI: 10.1080/23744235.2019.1634281]

[22] Busatto C, Vianna JS, da Silva LV, Ramis IB, da Silva PEA. Mycobacterium avium: an overview. Tuberculosis 2019; 114: 127-34. [PMID: 30711152 DOI: 10.1016/j.tube.2018.12.004]

[23] Gutierrez C, Somoskovi A. Human pathogenic mycobacteria. In: Reference Module in Biomedical Sciences. Third Edition. Elsevier; 2014. pp. 1-15.

[24] Lee MR, Sheng WH, Hung CC, Yu CJ, Lee LN, et al. Mycobacterium abscessus complex infections in humans. Emerg Infect Dis 2015; 21(9): 1638-46. [PMID: 26295364 DOI: 10.3201/2109.141634]

[25] Okamori S, Asakura T, Nishimura T, Tamizu E, Ishii M, et al. Natural history of Mycobacterium fortuitum pulmonary infection presenting with migratory infiltrates: a case report with microbiological analysis. BMC Infect Dis 2018; 18(1): 1. [PMID: 29291713 DOI: 10.1186/s12879-017-2892-9]

[26] Johansen MD, Herrmann JL, Kremer L. Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus . Nat Rev Microbiol 2020; 18(7): 392-407. [PMID: 32086501 DOI: 10.1038/s41579-020-0331-1]

[27] Gopalaswamy R, Shanmugam S, Mondal R, Subbian S. Of tuberculosis and non-tuberculous mycobacterial infections - a comparative analysis of epidemiology, diagnosis and treatment. J Biomed Sci 2020; 27(1): 74. [PMID: 32552732 DOI: 10.1186/s12929-020-00667-6]

[28] Nguta JM, Appiah-Opong R, Nyarko AK, Yeboah-Manu D, Addo PGA. Current perspectives in drug discovery against tuberculosis from natural products. Int J Mycobacteriol 2015; 4(3): 165-83. [PMID: 27649863 DOI: 10.1016/j.ijmyco.2015.05.004]

[29] Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov 2013; 12(5): 388-404. [PMID: 23629506 DOI: 10.1038/nrd4001]

[30] Kumar G, Kapoor S. Targeting mycobacterial membranes and membrane proteins: progress and limitations. Bioorg Med Chem 2023; 81: 117212. [PMID: 36804747 DOI: 10.1016/j.bmc.2023.117212]

[31] Kumar G, Adhikrao PA. Targeting Mycobacterium tuberculosis iron-scavenging tools: a recent update on siderophores inhibitors. RSC Med Chem 2023; 14(10): 1885-913. [PMID: 37859726 DOI: 10.1039/d3md00201b]

[32] Kumar G, Amrutha C. Natural products and their analogues acting against Mycobacterium tuberculosis: a recent update. Drug Dev Res 2023; 84(5): 779-804. [PMID: 37086027 DOI: 10.1002/ddr.22063]

[33] Soni I, De Groote MA, Dasgupta A, Chopra S. Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria. J Med Microbiol 2016; 65(1): 1-8. [PMID: 26515915 DOI: 10.1099/jmm.0.000198]

[34] Coolen N, Morand P, Martin C, Hubert D, Kanaan R, et al. Reduced risk of nontuberculous mycobacteria in cystic fibrosis adults receiving long-term azithromycin. J Cyst Fibros 2015; 14(5): 594-9. [PMID: 25735458 DOI: 10.1016/j.jcf.2015.02.006]

[35] van Ingen J. Treatment of pulmonary disease caused by non-tuberculous mycobacteria. Lancet Respir Med 2015; 3(3): 179-80. [PMID: 25773208 DOI: 10.1016/S2213-2600(15)00033-8]

[36] Palencia A, Li X, Bu W, Choi W, Ding CZ, et al. Discovery of novel oral protein synthesis inhibitors of mycobacterium tuberculosis that target leucyl-tRNA synthetase. Antimicrob Agents Chemother 2016; 60(10): 6271-80. [PMID: 27503647 DOI: 10.1128/AAC.01339-16]

[37] Raaijmakers J, Schildkraut JA, Hoefsloot W, van Ingen J. The role of amikacin in the treatment of nontuberculous mycobacterial disease. Expert Opin Pharmacother 2021; 22(15): 1961-74. [PMID: 34292097 DOI: 10.1080/14656566.2021.1953472]

[38] Kim TS, Choe JH, Kim YJ, Yang CS, Kwon HJ, et al. Activity of LCB01-0371, a novel oxazolidinone, against Mycobacterium abscessus . Antimicrob Agents Chemother 2017; 61(9): e02752. [PMID: 28674049 DOI: 10.1128/AAC.02752-16]

[39] Brown-Elliott BA, Wallace RJ. In vitro susceptibility testing of tedizolid against nontuberculous mycobacteria. J Clin Microbiol 2017; 55(6): 1747-54. [PMID: 28330892 DOI: 10.1128/JCM.00274-17]

[40] Brown-Elliott BA, Wallace RJ. In vitro susceptibility testing of eravacycline against nontuberculous mycobacteria. Antimicrob Agents Chemother 2022; 65(3): e0068922. [PMID: 35943269 DOI: 10.1128/aac.00689-22]

[41] Alffenaar JW, Märtson AG, Heysell SK, Cho JG, Patanwala A, et al. Therapeutic drug monitoring in non-tuberculosis mycobacteria infections. Clin Pharmacokinet 2021; 60(6): 711-25. [PMID: 33751415 DOI: 10.1007/s40262-021-01000-6]

[42] Muñoz-Egea MC, Carrasco-Antón N, Esteban J. State-of-the-art treatment strategies for nontuberculous mycobacteria infections. Expert Opin Pharmacother 2020; 21(8): 969-81. [PMID: 32200657 DOI: 10.1080/14656566.2020.1740205]

[43] Locher CP, Jones SM, Hanzelka BL, Perola E, Shoen CM, et al. A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections. Antimicrob Agents Chemother 2015; 59(3): 1455-65. [PMID: 25534737 DOI: 10.1128/AAC.04347-14]

[44] Brown-Elliott BA, Rubio A, Wallace RJ. In vitro susceptibility testing of a novel benzimidazole, SPR719, against nontuberculous mycobacteria. Antimicrob Agents Chemother 2018; 62(11): e01503-18. [PMID: 30126964 DOI: 10.1128/AAC.01503-18]

[45] Stokes SS, Vemula R, Pucci MJ. Advancement of GyrB inhibitors for treatment of infections caused by Mycobacterium tuberculosis and non-tuberculous mycobacteria. ACS Infect Dis 2020; 6(6): 1323-31. [PMID: 32183511 DOI: 10.1021/acsinfecdis.0c00025]

[46] Aziz DB, Low JL, Wu ML, Gengenbacher M, Teo JWP, et al. Rifabutin is active against Mycobacterium abscessus complex. Antimicrob Agents Chemother 2017; 61(6): 1-17. [PMID: 28396540 DOI: 10.1128/AAC.00155-17]

[47] Kim DH, Kim SY, Huh HJ, Lee NY, Koh WJ, et al. In vitro activity of rifamycin derivatives against nontuberculous mycobacteria, including macrolide- and amikacin-resistant clinical isolates. Antimicrob Agents Chemother 2021; 65(5): e02611-20. [PMID: 33685889 DOI: 10.1128/AAC.02611-20]

[48] Kim DH, Jhun BW, Moon SM, Kim SY, Jeon K, et al. In vitro activity of bedaquiline and delamanid against nontuberculous mycobacteria, including macrolide-resistant clinical isolates. Antimicrob Agents Chemother 2019; 63(8): e00665-19. [PMID: 31182533 DOI: 10.1128/AAC.00665-19]

[49] Pfaeffle HOI, Alameer RM, Marshall MH, Houpt ER, Albon DP, et al. Clofazimine for treatment of multidrug-resistant non-tuberculous mycobacteria. Pulm Pharmacol Ther 2021; 70: 102058. [PMID: 34293446 DOI: 10.1016/j.pupt.2021.102058]

[50] Kumar G, Engle K. Natural products acting against S. aureus through membrane and cell wall disruption. Nat Prod Rep 2023; 40(10): 1608-46. [DOI: 10.1039/D2NP00084A]

[51] Muñoz-Muñoz L, Aínsa JA, Ramón-García S. Repurposing β-lactams for the treatment of Mycobacterium kansasii infections: an in vitro study. Antibiotics 2023; 12(2): 335. [PMID: 36830246 DOI: 10.3390/antibiotics12020335]

[52] Lefebvre AL, Le Moigne V, Bernut A, Veckerlé C, Compain F, et al. Inhibition of the β-lactamase BlaMab by avibactam improves the in vitro and in vivo efficacy of imipenem against Mycobacterium abscessus . Antimicrob Agents Chemother 2017; 61(4): e02440. [PMID: 28096155 DOI: 10.1128/AAC.02440-16]

[53] Negatu DA, González del Río R, Cacho-Izquierdo M, Barros-Aguirre D, Lelievre J, et al. Activity of oral tebipenem-avibactam in a mouse model of Mycobacterium abscessus lung infection. Antimicrob Agents Chemother 2023; 67(2): e0145922. [PMID: 36688684 DOI: 10.1128/aac.01459-22]

[54] Le Run E, Atze H, Arthur M, Mainardi JL . Impact of relebactam-mediated inhibition of Mycobacterium abscessus BlaMab β-lactamase on the in vitro and intracellular efficacy of imipenem. J Antimicrob Chemother 2019; 75(2): 379-83. [PMID: 31637424 DOI: 10.1093/jac/dkz433]

[55] Kaushik A, Ammerman NC, Parrish NM, Nuermberger EL. New β-lactamase inhibitors nacubactam and zidebactam improve the in vitro activity of β-lactam antibiotics against Mycobacterium abscessus complex clinical isolates. Antimicrob Agents Chemother 2019; 63(9): e00733-19. [PMID: 31209013 DOI: 10.1128/AAC.00733-19]

[56] Seung KJ, Keshavjee S, Rich ML. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harb Perspect Med 2015; 5(9): a017863. [PMID: 25918181 DOI: 10.1101/cshperspect.a017863]

[57] Tran T, Bonham AJ, Chan ED, Honda JR. A paucity of knowledge regarding nontuberculous mycobacterial lipids compared to the tubercle bacillus. Tuberculosis 2019; 115: 96-107. [PMID: 30948183 DOI: 10.1016/j.tube.2019.02.008]

[58] World Health Organization . WHO Bacterial Priority Pathogens List, 2024:Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. 2024.

[59] Mabhula A, Singh V. Drug-resistance in Mycobacterium tuberculosis: where we stand. Medchemcomm 2019; 10(8): 1342-60. [PMID: 31534654 DOI: 10.1039/c9md00057g]

[60] Singh R, Dwivedi SP, Gaharwar US, Meena R, Rajamani P, et al. Recent updates on drug resistance in Mycobacterium tuberculosis . J Appl Microbiol 2020; 128(6): 1547-67. [PMID: 31595643 DOI: 10.1111/jam.14478]

[61] Smith T, Wolff KA, Nguyen L. Molecular biology of drug resistance in Mycobacterium tuberculosis . Curr Top Microbiol Immunol 2013; 374: 53-80. [PMID: 23179675 DOI: 10.1007/82_2012_279]

[62] Poulton NC, Rock JM. Unraveling the mechanisms of intrinsic drug resistance in Mycobacterium tuberculosis . Front Cell Infect Microbiol 2022; 12: 997283. [PMID: 36325467 DOI: 10.3389/fcimb.2022.997283]

[63] Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, Murray M, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017; 5(4): 291-360. [DOI: 10.1016/S2213-2600(17)30079-6]

[64] Saxena S, Spaink HP, Forn-Cuní G. Drug resistance in nontuberculous mycobacteria: mechanisms and models. Biology (Basel) 2021; 10(2): 96. [PMID: 33573039 DOI: 10.3390/biology10020096]

[65] Sachan RSK, Mistry V, Dholaria M, Rana A, Devgon I, et al. Overcoming Mycobacterium tuberculosis drug resistance: novel medications and repositioning strategies. ACS Omega 2023; 8(36): 32244-57. [PMID: 37720746 DOI: 10.1021/acsomega.3c02563]

[66] Song L, Wu X. Development of efflux pump inhibitors in antituberculosis therapy. Int J Antimicrob Agents 2016; 47(6): 421-9. [PMID: 27211826 DOI: 10.1016/j.ijantimicag.2016.04.007]

[67] Domínguez J, Boettger EC, Cirillo D, Cobelens F, Eisenach KD, et al. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement. Int J Tuberc Lung Dis 2016; 20(1): 24-42. [PMID: 26688526 DOI: 10.5588/ijtld.15.0221]

[68] Dookie N, Rambaran S, Padayatchi N, Mahomed S, Naidoo K. Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care. J Antimicrob Chemother 2018; 73(5): 1138-51. [PMID: 29360989 DOI: 10.1093/jac/dkx506]

[69] 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): 1417-30. [PMID: 21558086 DOI: 10.1093/jac/dkr173]

[70] Danilchanka O, Pires D, Anes E, Niederweis M. The Mycobacterium tuberculosis outer membrane channel protein cpnt confers susceptibility to toxic molecules. Antimicrob Agents Chemother 2015; 59(4): 2328-36. [PMID: 25645841 DOI: 10.1128/AAC.04222-14]

[71] Tseng ST, Tai CH, Li CR, Lin CF, Shi ZY. The mutations of katG and inhA genes of isoniazid-resistant Mycobacterium tuberculosis isolates in Taiwan. J Microbiol Immunol Infect 2015; 48(3): 249-55. [PMID: 24184004 DOI: 10.1016/j.jmii.2013.08.018]

[72] Bakhtiyariniya P, Khosravi AD, Hashemzadeh M, Savari M. Detection and characterization of mutations in genes related to isoniazid resistance in Mycobacterium tuberculosis clinical isolates from Iran. Mol Biol Rep 2022; 49(7): 6135-43. [PMID: 35366177 DOI: 10.1007/s11033-022-07404-2]

[73] Viswanathan G, Yadav S, Raghunand TR. Identification of novel loci associated with mycobacterial isoniazid resistance. Tuberculosis 2016; 96: 21-6. [PMID: 26786650 DOI: 10.1016/j.tube.2015.09.008]

[74] Yimcharoen M, Saikaew S, Wattananandkul U, Phunpae P, Intorasoot S, et al. The regulation of ManLAM-related gene expression in Mycobacterium tuberculosis with different drug resistance profiles following isoniazid treatment. Infect Drug Resist 2022; 15: 399-412. [PMID: 35153492 DOI: 10.2147/IDR.S346869]

[75] Alifano P, Palumbo C, Pasanisi D, Talà A. Rifampicin-resistance, rpoB polymorphism and RNA polymerase genetic engineering. J Biotechnol 2015; 202: 60-77. [PMID: 25481100 DOI: 10.1016/j.jbiotec.2014.11.024]

[76] de Knegt GJ, Bruning O, ten Kate MT, de Jong M, van Belkum A, et al. Rifampicin-induced transcriptome response in rifampicin-resistant Mycobacterium tuberculosis . Tuberculosis 2013; 93(1): 96-101. [PMID: 23182912 DOI: 10.1016/j.tube.2012.10.013]

[77] Zaw MT, Emran NA, Lin Z. Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis . J Infect Public Health 2018; 11(5): 605-10. [PMID: 29706316 DOI: 10.1016/j.jiph.2018.04.005]

[78] Casali N, Nikolayevskyy V, Balabanova Y, Harris SR, Ignatyeva O, et al. Evolution and transmission of drug-resistant tuberculosis in a Russian population. Nat Genet 2014; 46(3): 279-86. [PMID: 24464101 DOI: 10.1038/ng.2878]

[79] Merker M, Kohl TA, Barilar I, Andres S, Fowler PW, et al. Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex. Genome Med 2020; 12(1): 27. [PMID: 32143680 DOI: 10.1186/s13073-020-00726-5]

[80] Junaid M, Khan MT, Malik SI, Wei DQ. Insights into the mechanisms of the pyrazinamide resistance of three pyrazinamidase mutants N11K, P69T, and D126N. J Chem Inf Model 2019; 59(1): 498-508. [PMID: 30481017 DOI: 10.1021/acs.jcim.8b00525]

[81] Miotto P, Cabibbe AM, Feuerriegel S, Casali N, Drobniewski F, et al. Mycobacterium tuberculosis pyrazinamide resistance determinants: a multicenter study. mBio 2014; 5(5):e01819-14. [PMID: 25336456 DOI: 10.1128/ mBio.01819-14]

[82] Sheen P, Requena D, Gushiken E, Gilman RH, Antiparra R, et al. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance. BMC Genomics 2017; 18(1): 769. [PMID: 29020922 DOI: 10.1186/s12864-017-4146-z]

[83] Zhang L, Zhao Y, Gao Y, Wu L, Gao R, et al. Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol. Science 2020; 368(6496): 1211-9. [PMID: 32327601 DOI: 10.1126/science.aba9102]

[84] Xu Y, Jia H, Huang H, Sun Z, Zhang Z. Mutations found in embCAB, embR, and ubiA genes of ethambutol-sensitive and -resistant Mycobacterium tuberculosis clinical isolates from China. Biomed Res Int 2015; 2015: 951706. [PMID: 26417605 DOI: 10.1155/2015/951706]

[85] He L, Wang X, Cui P, Jin J, Chen J, et al. ubiA (Rv3806c) encoding DPPR synthase involved in cell wall synthesis is associated with ethambutol resistance in Mycobacterium tuberculosis . Tuberculosis 2015; 95(2): 149-54. [PMID: 25547657 DOI: 10.1016/j.tube.2014.12.002]

[86] Brossier F, Sougakoff W, Bernard C, Petrou M, Adeyema K, et al. Molecular analysis of the embCAB locus and embR gene involved in ethambutol resistance in clinical isolates of Mycobacterium tuberculosis in France. Antimicrob Agents Chemother 2015; 59(8): 4800- 8. [PMID: 26033726 DOI: 10.1128/AAC.00150-15]

[87] Zhao LL, Sun Q, Liu HC, Wu XC, Xiao TY, et al. Analysis of embCAB mutations associated with ethambutol resistance in multidrug-resistant Mycobacterium tuberculosis isolates from China. Antimicrob Agents Chemother 2015; 59(4): 2045-50. [PMID: 25605360 DOI: 10.1128/AAC.04933-14]

[88] Shippy DC, Fadl AA. RNA modification enzymes encoded by the gid operon: Implications in biology and virulence of bacteria. Microb Pathog 2015; 89: 100-7. [DOI: 10.1016/j.micpath.2015.09.008]

[89] Hlaing YM, Tongtawe P, Tapchaisri P, Thanongsaksrikul J, Thawornwan U, et al. Mutations in streptomycin resistance genes and their relationship to streptomycin resistance and lineage of Mycobacterium tuberculosis thai isolates. Tuberc Respir Dis (Seoul) 2017; 80(2): 159. [PMID: 28416956 DOI: 10.4046/trd.2017.80.2.159]

[90] Reeves AZ, Campbell PJ, Sultana R, Malik S, Murray M, et al. Aminoglycoside cross-resistance in Mycobacterium tuberculosis due to mutations in the 5′ untranslated region of whiB7. Antimicrob Agents Chemother 2013; 57(4): 1857-65. [PMID: 23380727 DOI: 10.1128/AAC.02191-12]

[91] Batson S, De Chiara C, Majce V, Lloyd AJ, Gobec S, et al. Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine. Nat Commun 2017; 8(1): 1939. [DOI: 10.1038/s41467-017-02118-7]

[92] Chen J, Zhang S, Cui P, Shi W, Zhang W, et al. Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis . J Antimicrob Chemother 2017; 72(12): 3272-6. [PMID: 28961957 DOI: 10.1093/jac/dkx316]

[93] Malik S, Willby M, Sikes D, Tsodikov OV, Posey JE. New insights into fluoroquinolone resistance in Mycobacterium tuberculosis: functional genetic analysis of gyrA and gyrB mutations. PLoS One 2012; 7(6): e39754. [PMID: 22761889 DOI: 10.1371/journal.pone.0039754]

[94] Eilertson B, Maruri F, Blackman A, Guo Y, Herrera M, et al. A novel resistance mutation in eccC₅ of the ESX-5 secretion system confers ofloxacin resistance in Mycobacterium tuberculosis . J Antimicrob Chemother 2016; 71(9): 2419-27. [PMID: 27261264 DOI: 10.1093/jac/dkw168]

[95] Aragaw WW, Cotroneo N, Stokes S, Pucci M, Critchley I, et al. In vitro resistance against DNA gyrase inhibitor SPR719 in Mycobacterium avium and Mycobacterium abscessus . Microbiol Spectr 2022; 10(1): e0132121. [PMID: 35019671 DOI: 10.1128/spectrum.01321-21]

[96] Durcik M, Tomašič T, Zidar N, Zega A, Kikelj D, et al. ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents. Expert Opin Ther Pat 2019; 29(3): 171-80. [PMID: 30686070 DOI: 10.1080/13543776.2019.1575362]

[97] Preiss L, Langer JD, Yildiz Ö, Eckhardt-Strelau L, Guillemont JEG, et al. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci Adv 2015; 1(4): e1500106. [PMID: 26601184 DOI: 10.1126/sciadv.1500106]

[98] Andries K, Villellas C, Coeck N, Thys K, Gevers T, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One 2014; 9(7): e102135. [PMID: 25010492 DOI: 10.1371/journal.pone.0102135]

[99] Almeida D, Ioerger T, Tyagi S, Li SY, Mdluli K, et al. Mutations in pepQ confer low-level resistance to bedaquiline and clofazimine in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2016; 60(8): 4590-9. [PMID: 27185800 DOI: 10.1128/AAC.00753-16]

[100] Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012; 2151-60. [PMID: 22670901 DOI: 10.1056/NEJMoa1112433]

[101] Ryan NJ, Lo JH. Delamanid: first global approval. Drugs 2014; 74(9): 1041-5. [PMID: 24923253 DOI: 10.1007/s40265-014-0241-5]

[102] Blair HA, Scott LJ. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Drugs 2015; 75(1): 91-100. [PMID: 25404020 DOI: 10.1007/s40265-014-0331-4]

[103] Nguyen TVA, Anthony RM, Cao TTH, Bañuls AL, Nguyen VAT, et al. Delamanid resistance: update and clinical management. Clin Infect Dis 2020; 71(12): 3252-9. [PMID: 32521000 DOI: 10.1093/cid/ciaa755]

[104] Fujiwara M, Kawasaki M, Hariguchi N, Liu Y, Matsumoto M. Mechanisms of resistance to delamanid, a drug for Mycobacterium tuberculosis . Tuberculosis 2018; 108: 186-94. [PMID: 29523322 DOI: 10.1016/j.tube.2017.12.006]

[105] Liu Y, Shi J, Li L, Wu T, Chu P, et al. Spontaneous mutational patterns and novel mutations for delamanid resistance in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2022; 66(12): e0053122. [PMID: 36448833 DOI: 10.1128/aac.00531-22]

[106] Rifat D, Li SY, Ioerger T, Shah K, Lanoix JP, et al. Mutations in fbiD (Rv2983) as a novel determinant of resistance to pretomanid and delamanid in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2021; 65(1): e01948. [PMID: 33077652 DOI: 10.1128/AAC.01948-20]

[107] Batt SM, Jabeen T, Bhowruth V, Quill L, Lund PA, et al. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc Natl Acad Sci U S A 2012; 109(28): 11354-9. [PMID: 22733761 DOI: 10.1073/pnas.1205735109]

[108] Brecik M, Centárová I, Mukherjee R, Kolly GS, Huszár S, et al. DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization. ACS Chem Biol 2015; 10(7): 1631-6. [PMID: 25906160 DOI: 10.1021/acschembio.5b00237]

[109] Poulton NC, Azadian ZA, DeJesus MA, Rock JM. Mutations in rv0678 confer low-level resistance to benzothiazinone DprE1 inhibitors in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2022; 66(9): e0090422. [PMID: 35920665 DOI: 10.1128/aac.00904-22]

[110] Ye M, Xu L, Zou Y, Li B, Guo Q, et al. Molecular analysis of linezolid-resistant clinical isolates of Mycobacterium abscessus . Antimicrob Agents Chemother 2019; 63(2): e01842-18. [PMID: 30478161 DOI: 10.1128/AAC.01842-18]

[111] Luthra S, Rominski A, Sander P. The role of antibiotic-target-modifying and antibiotic-modifying enzymes in Mycobacterium abscessus drug resistance. Front Microbiol 2018; 9: 2179. [PMID: 30258428 DOI: 10.3389/fmicb.2018.02179]

[112] Fisher JF, Mobashery S. β-Lactam resistance mechanisms: gram-positive bacteria and Mycobacterium tuberculosis . Cold Spring Harb Perspect Med 2016; 6(5): a025221. [PMID: 27091943 DOI: 10.1101/cshperspect.a025221]

[113] Witek MA, Kuiper EG, Minten E, Crispell EK, Conn GL. A novel motif for S-adenosyl-l-methionine binding by the ribosomal RNA methyltransferase TlyA from Mycobacterium tuberculosis . J Biol Chem 2017; 292(5): 1977-87. [PMID: 28031456 DOI: 10.1074/jbc.M116.752659]

[114] Laughlin ZT, Nandi S, Dey D, Zelinskaya N, Witek MA, et al. 50S subunit recognition and modification by the Mycobacterium tuberculosis ribosomal RNA methyltransferase TlyA. Proc Natl Acad Sci 2022; 119(14): e212035119. [PMID: 35357969 DOI: 10.1073/pnas.2120352119]

[115] Richard M, Gutiérrez AV, Kremer L . Dissecting erm(41)-mediated macrolide-inducible resistance in Mycobacterium abscessus . Antimicrob Agents Chemother 2020; 64(2): e01879-19. [PMID: 31791943 DOI: 10.1128/AAC.01879-19]

[116] Griffith DE, Daley CL. Treatment of Mycobacterium abscessus pulmonary disease. Chest 2022; 161(1): 64-75. [PMID: 34314673 DOI: 10.1016/j.chest.2021.07.035]

[117] Rominski A, Roditscheff A, Selchow P, Böttger EC, Sander P. Intrinsic rifamycin resistance of Mycobacterium abscessus is mediated by ADP-ribosyltransferase MAB_0591. J Antimicrob Chemother 2017; 72(2): 376-84. [PMID: 27999011 DOI: 10.1093/jac/dkw466]

[118] Chuang YM, Bandyopadhyay N, Rifat D, Rubin H, Bader JS, et al. Deficiency of the novel exopolyphosphatase Rv1026/PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis . mBio 2015; 6(2): e02428. [PMID: 25784702 DOI: 10.1128/mBio.02428-14]

[119] Hajiagha MN, Kafil HS. Efflux pumps and microbial biofilm formation. Infect Genet Evol 2023; 115: 105459. [PMID: 37271271 DOI: 10.1016/j.meegid.2023.105459]

[120] Fouladi MD, Besharati S, Farnia P, Khosravi A. A concise review of the effect of efflux pump on biofilm intensity in bacteria with a special view to Mycobacterium . J Prev Diagn Treat Strate Med 2024; 3(1): 1-5. [DOI: 10.4103/jpdtsm.jpdtsm_119_23]

[121] Li P, Gu Y, Li J, Xie L, Li X, et al. Mycobacterium tuberculosis major facilitator superfamily transporters. J Membr Biol 2017; 250(6): 573-85. [PMID: 28852815 DOI: 10.1007/s00232-017-9982-x]

[122] Kanji A, Hasan R, Hasan Z. Efflux pump as alternate mechanism for drug resistance in Mycobacterium tuberculosis . Indian J Tuberc 2019; 66(1): 20-5. [PMID: 30797276 DOI: 10.1016/j.ijtb.2018.07.008]

[123] Balganesh M, Dinesh N, Sharma S, Kuruppath S, Nair AV, et al. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates. Antimicrob Agents Chemother 2012; 56(5): 2643-51. [PMID: 22314527 DOI: 10.1128/AAC.06003-11]

[124] Papkou A, Hedge J, Kapel N, Young B, MacLean RC. Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates. Nat Commun 2020; 11(1): 3970. [PMID: 32769975 DOI: 10.1038/s41467-020-17735-y]

[125] Briffotaux J, Huang W, Wang X, Gicquel B. MmpS5/MmpL5 as an efflux pump in Mycobacterium species. Tuberculosis 2017; 107: 13-9. [PMID: 29050760 DOI: 10.1016/j.tube.2017.08.001]

[126] Kumar G, Kiran Tudu A . Tackling multidrug-resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors. Bioorg Med Chem 2023; 80: 117187. [PMID: 36731248 DOI: 10.1016/j.bmc.2023.117187]

[127] Kanji A, Hasan R, Ali A, Zaver A, Zhang Y, et al. Single nucleotide polymorphisms in efflux pumps genes in extensively drug resistant Mycobacterium tuberculosis isolates from Pakistan. Tuberculosis 2017; 107: 20-30. [PMID: 29050768 DOI: 10.1016/j.tube.2017.07.012]

[128] Coll F, Phelan J, Hill-Cawthorne GA, Nair MB, Mallard K, et al. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis . Nat Genet 2018; 50(2): 307-16. [PMID: 29358649 DOI: 10.1038/s41588-017-0029-0]

[129] Duan W, Li X, Ge Y, Yu Z, Li P, et al. Mycobacterium tuberculosis Rv1473 is a novel macrolides ABC efflux pump regulated by WhiB7. Future Microbiol 2019; 14(1): 47-59. [PMID: 30539658 DOI: 10.2217/fmb-2018-0207]

[130] De Siena B, Campolattano N, D’Abrosca G, Russo L, Cantillon D, et al. Characterization of the mycobacterial MSMEG-3762/63 efflux pump in Mycobacterium smegmatis drug efflux. Front Microbiol 2020; 11: 575828. [PMID: 33343518 DOI: 10.3389/fmicb.2020.575828]

[131] Wang K, Pei H, Huang B, Zhu X, Zhang J, et al. The expression of ABC efflux pump, Rv1217c-Rv1218c, and its association with multidrug resistance of Mycobacterium tuberculosis in China. Curr Microbiol 2013; 66(3): 222-6. [PMID: 23143285 DOI: 10.1007/s00284-012-0215-3]

[132] Ma F, Zhou H, Yang Z, Wang C, An Y, et al. Gene expression profile analysis and target gene discovery of Mycobacterium tuberculosis biofilm. Appl Microbiol Biotechnol 2021; 105(12): 5123-34. [PMID: 34125278 DOI: 10.1007/s00253-021-11361-4]

[133] Liu J, Shi W, Zhang S, Hao X, Maslov DA, et al. Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide, isoniazid, and streptomycin in M. tuberculosis . Front Microbiol 2019; 10: 216. [PMID: 30837962 DOI: 10.3389/fmicb.2019.00216]

[134] Cloete R, Kapp E, Joubert J, Christoffels A, Malan SF. Correction: Molecular modelling and simulation studies of the Mycobacterium tuberculosis multidrug efflux pump protein Rv1258c. PLoS One 2018; 13(11): e0207605. [PMID: 30475855 DOI: 10.1371/journal.pone.0209717]

[135] Johnson EO, Office E, Kawate T, Orzechowski M, Hung DT. Large-scale chemical-genetic strategy enables the design of antimicrobial combination chemotherapy in mycobacteria. ACS Infect Dis 2020; 6(1): 56-63. [PMID: 31721551 DOI: 10.1021/acsinfecdis.9b00373]

[136] Johnson EO, LaVerriere E, Office E, Stanley M, Meyer E, et al. Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes. Nature 2019; 571(7763): 72-8. [PMID: 31217586 DOI: 10.1038/s41586-019-1315-z]

[137] Wang S, Wang K, Song K, Lai ZW, Li P, Li D, et al. Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition. Nat Commun 2024; 15(1): 7710. [PMID: 39231991 DOI: 10.1038/s41467-024-51948-9]

[138] Umar F, Hatta M, Husain DR, Natzir R, Dwiyanti R, et al. The effect of anti-tuberculosis drugs therapy on mRNA efflux pump gene expression of Rv1250 in Mycobacterium tuberculosis collected from tuberculosis patients. New Microbes New Infect 2019; 32: 100609. [PMID: 33014381 DOI: 10.1016/j.nmni.2019.100609]

[139] Li X, Li P, Ruan C, Xie LX, Gu Y, et al. Mycobacterium tuberculosis Rv0191 is an efflux pump of major facilitator superfamily transporter regulated by Rv1353c. Arch Biochem Biophys 2019; 667(May): 59-66. [PMID: 31054279 DOI: 10.1016/j.abb.2019.04.010]

[140] Thakur V, Uniyal A, Tiwari V. A comprehensive review on pharmacology of efflux pumps and their inhibitors in antibiotic resistance. Eur J Pharmacol 2021; 903: 174151. [PMID: 33964293 DOI: 10.1016/j.ejphar.2021.174151]

[141] Rai D, Mehra S. The mycobacterial efflux pump EfpA can induce high drug tolerance to many antituberculosis drugs, including moxifloxacin, in Mycobacterium smegmatis . Antimicrob Agents Chemother 2021; 65(11): e0026221. [PMID: 34424047 DOI: 10.1128/AAC.00262-21]

[142] Zhang Z, Wang R, Xie J. Mycobacterium smegmatis MSMEG_3705 encodes a selective major facilitator superfamily efflux pump with multiple roles. Curr Microbiol 2015; 70(6): 801-9. [PMID: 25697715 DOI: 10.1007/s00284-015-0783-0]

[143] Mörs K, Hellmich UA, Basting D, Marchand P, Wurm JP, Haase W, et al. A lipid-dependent link between activity and oligomerization state of the M. tuberculosis SMR protein TBsmr. Biochim Biophys Acta 2013; 1828(2): 561-7. [PMID: 23103507 DOI: 10.1016/j.bbamem.2012.10.020]

[144] Machado D, Lecorche E, Mougari F, Cambau E, Viveiros M. Insights on Mycobacterium leprae efflux pumps and their implications in drug resistance and virulence. Front Microbiol 2018; 9: 3072. [PMID: 30619157 DOI: 10.3389/fmicb.2018.03072]

[145] Rodrigues L, Villellas C, Bailo R, Viveiros M, Aínsa JA. Role of the mmr efflux pump in drug resistance in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2013; 57(2): 751-7. [PMID: 23165464 DOI: 10.1128/AAC.01482-12]

[146] Unissa AN, Dusthackeer VNA, Kumar MP, Nagarajan P, Sukumar S, et al. Variants of katG, inhA and nat genes are not associated with mutations in efflux pump genes (mmpL3 and mmpL7) in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India. Tuberculosis 2017; 107: 144-8. [PMID: 29050763 DOI: 10.1016/j.tube.2017.07.014]

[147] Gutiérrez AV, Richard M, Roquet-Banères F, Viljoen A, Kremer L. The TetR family transcription factor MAB_2299c regulates the expression of two distinct MmpS-MmpL efflux pumps involved in cross-resistance to clofazimine and bedaquiline in Mycobacterium abscessus . Antimicrob Agents Chemother 2019; 63(10): e01000-19. [PMID: 31332077 DOI: 10.1128/AAC.01000-19]

[148] Yamamoto K, Nakata N, Mukai T, Kawagishi I, Ato M. Coexpression of MmpS5 and MmpL5 contributes to both efflux transporter MmpL5 trimerization and drug resistance in Mycobacterium tuberculosis . mSphere 2021; 6(1): e00518. [PMID: 33408221 DOI: 10.1128/mSphere.00518-20]

[149] Farnia P, Besharati S, Farina P, Ayoubi S, Marjani M, et al. The role of efflux pumps transporter in multi-drug resistant tuberculosis: mycobacterial memberane protein(MmpL5). Int J Mycobacteriol 2024; 13(1): 7-14. [PMID: 38771273 DOI: 10.4103/ijmy.ijmy_37_24]

[150] 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): 2979-81. [PMID: 24590481 DOI: 10.1128/AAC.00037-14]

[151] Li M, Nyantakyi SA, Go ML, Dick T. Resistance against membrane-inserting MmpL3 inhibitor through upregulation of MmpL5 in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2020; 64(12): e01100-20. [PMID: 32958714 DOI: 10.1128/AAC.01100-20]

[152] Shur KV, Frolova SG, Akimova NI, Danilenko VN, Maslov DA. A test system for in vitro screening antimycobacterial drug candidates for MmpS5-MmpL5 mediated resistance. Russ J Genet 2021; 57(1): 114-6. [DOI: 10.1134/S1022795421010154]

[153] Guo Q, Chen J, Zhang S, Zou Y, Zhang Y, et al. Efflux pumps contribute to intrinsic clarithromycin resistance in clinical, Mycobacterium abscessus isolates. Infect Drug Resist 2020; 13: 447-54. [PMID: 32104016 DOI: 10.2147/IDR.S239850]

[154] Guo Q, Zhang Y, Fan J, Zhang H, Zhang Z, et al. MAB_2355c confers macrolide resistance in Mycobacterium abscessus by ribosome protection. Antimicrob Agents Chemother 2021; 65(8): e0033021. [PMID: 34097497 DOI: 10.1128/AAC.00330-21]

[155] Vianna JS, Machado D, Ramis IB, Silva FP, Bierhals DV, et al. The contribution of efflux pumps in Mycobacterium abscessus complex resistance to clarithromycin. Antibiotics 2019; 8(3): 153. [PMID: 31540480 DOI: 10.3390/antibiotics8030153]

[156] Rodrigues L, Machado D, Couto I, Amaral L, Viveiros M. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect Genet Evol 2012; 12(4): 695-700. [PMID: 21871582 DOI: 10.1016/j.meegid.2011.08.009]

[157] Gupta AK, Reddy VP, Lavania M, Chauhan DS, Venkatesan K, et al. jefA (Rv2459), a drug efflux gene in Mycobacterium tuberculosis confers resistance to isoniazid & ethambutol. Indian J Med Res 2010; 132(8): 176-88. [PMID: 20716818]

[158] Zhang Y, Zhang J, Cui P, Zhang Y, Zhang W. Identification of novel efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c involved in pyrazinamide resistance in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2017; 61(8): e00940-17. [PMID: 28584158 DOI: 10.1128/AAC.00940-17]

[159] Zimic M, Fuentes P, Gilman RH, Gutiérrez AH, Kirwan D, et al. Pyrazinoic acid efflux rate in Mycobacterium tuberculosis is a better proxy of pyrazinamide resistance. Tuberculosis 2012; 92(1): 84-91. [PMID: 22004792 DOI: 10.1016/j.tube.2011.09.002]

[160] Caleffi-Ferracioli KR, Amaral RCR, Demitto FO, Maltempe FG, Canezin PH, et al. Morphological changes and differentially expressed efflux pump genes in Mycobacterium tuberculosis exposed to a rifampicin and verapamil combination. Tuberculosis 2016; 97: 65-72. [PMID: 26980498 DOI: 10.1016/j.tube.2015.12.010]

[161] Narang A, Garima K, Porwal S, Bhandekar A, Shrivastava K, 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. [PMID: 31557231 DOI: 10.1371/journal.pone.0223163]

[162] Canezin PH, Caleffi-Ferracioli KR, Scodro RBL, Siqueira VLD, Pavan FR, et al. Intramacrophage Mycobacterium tuberculosis efflux pump gene regulation after rifampicin and verapamil exposure. J Antimicrob Chemother 2018; 73(7): 1770-6. [PMID: 29579201 DOI: 10.1093/jac/dky091]

[163] Li G, Zhang J, Guo Q, Wei J, Jiang Y, et al. Study of efflux pump gene expression in rifampicin-monoresistant Mycobacterium tuberculosis clinical isolates. J Antibiot (Tokyo) 2015; 68(7): 431-5. [PMID: 25690361 DOI: 10.1038/ja.2015.9]

[164] Machado D, Coelho TS, Perdigão J, Pereira C, Couto I, et al. Interplay between mutations and efflux in drug resistant clinical isolates of Mycobacterium tuberculosis . Front Microbiol 2017; 8: 711. [PMID: 28496433 DOI: 10.3389/fmicb.2017.00711]

[165] Pule CM, Sampson SL, Warren RM, Black PA, van Helden PD, et al. Efflux pump inhibitors: targeting mycobacterial efflux systems to enhance TB therapy. J Antimicrob Chemother 2016; 71(1): 17-26. [PMID: 26472768 DOI: 10.1093/jac/dkv316]

[166] Sharma S, Kalia NP, Suden P, Chauhan PS, Kumar M, et al. Protective efficacy of piperine against Mycobacterium tuberculosis . Tuberculosis 2014; 94(4): 389-96. [PMID: 24880706 DOI: 10.1016/j.tube.2014.04.007]

[167] Sharma S, Kumar M, Sharma S, Nargotra A, Koul S, et al. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis . J Antimicrob Chemother 2010; 65(8): 1694-701. [PMID: 20525733 DOI: 10.1093/jac/dkq186]

[168] Hegeto LA, Caleffi-Ferracioli KR, Nakamura-Vasconcelos SS, Almeida AL, Baldin VP, et al. In vitro combinatory activity of piperine and anti-tuberculosis drugs in Mycobacterium tuberculosis . Tuberculosis 2018; 111: 35-40. [PMID: 30029912 DOI: 10.1016/j.tube.2018.05.006]

[169] Jin J, Zhang JY, Guo N, Sheng H, Li L, et al. Farnesol, a potential efflux pump inhibitor in Mycobacterium smegmatis . Molecules 2010; 15(11): 7750-62. [PMID: 21042264 DOI: 10.3390/molecules15117750]

[170] Viveiros M, Martins M, Rodrigues L, Machado D, Couto I, et al. Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev Anti Infect Ther 2012; 10(9): 983-98. [PMID: 23106274 DOI: 10.1586/eri.12.89]

[171] Huang TS, Kunin CM, Wang HM, Yan BS, Huang SP, et al. Inhibition of the Mycobacterium tuberculosis reserpine-sensitive efflux pump augments intracellular concentrations of ciprofloxacin and enhances susceptibility of some clinical isolates. J Formos Med Assoc 2013; 112(12): 789-94. [PMID: 24331109 DOI: 10.1016/j.jfma.2012.03.009]

[172] Shaheen A, Afridi WA, Mahboob S, Sana M, Zeeshan N, et al. Reserpine is the new addition into the repertoire of AcrB efflux pump inhibitors. Mol Biol (Mosk). 2019; 53(4): 674-84. [PMID: 31397441 DOI: 10.1134/S0026898419040128].

[173] Gröblacher B, Kunert O, Bucar F. Compounds of Alpinia katsumadai as potential efflux inhibitors in Mycobacterium smegmatis . Bioorg Med Chem 2012; 20(8): 2701-6. [PMID: 22459211 DOI: 10.1016/j.bmc.2012.02.039]

[174] Nakamura de Vasconcelos SS, Caleffi-Ferracioli KR, Hegeto LA, Baldin VP, Nakamura CV, et al. Carvacrol activity & morphological changes in Mycobacterium tuberculosis . Future Microbiol 2018; 13(8): 877-88. [PMID: 29877104 DOI: 10.2217/fmb-2017-0232]

[175] Miladi H, Zmantar T, Chaabouni Y, Fedhila K, Bakhrouf A, et al. Antibacterial and efflux pump inhibitors of thymol and carvacrol against food-borne pathogens. Microb Pathog 2016; 99: 95-100. [PMID: 27521228 DOI: 10.1016/j.micpath.2016.08.008]

[176] Sieniawska E, Swatko-Ossor M, Sawicki R, Skalicka-Woźniak K, Ginalska G. Natural terpenes influence the activity of antibiotics against isolated Mycobacterium tuberculosis . Med Princ Pract 2017; 26(2): 108-12. [PMID: 27883995 DOI: 10.1159/000454680]

[177] Solnier J, Martin L, Bhakta S, Bucar F. Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species. Molecules 2020; 25(3): 734. [PMID: 32046221 DOI: 10.3390/molecules25030734]

[178] Tran HT, Solnier J, Pferschy-Wenzig EM, Kunert O, Martin L, et al. Antimicrobial and efflux pump inhibitory activity of carvotacetones from Sphaeranthus africanus against mycobacteria. Antibiotics 2020; 9(7): 390. [PMID: 32650510 DOI: 10.3390/antibiotics9070390]

[179] Bhagya N, Chandrashekar KR. Tetrandrine - a molecule of wide bioactivity. Phytochemistry 2016; 125: 5-13. [PMID: 26899361 DOI: 10.1016/j.phytochem.2016.02.005]

[180] Zhang Z, Yan J, Xu K, Ji Z, Li L. Tetrandrine reverses drug resistance in isoniazid and ethambutol dual drug-resistant Mycobacterium tuberculosis clinical isolates. BMC Infect Dis 2015; 15(1): 153. [PMID: 25887373 DOI: 10.1186/s12879-015-0905-0]

[181] Plášek J, Babuka D, Hoefer M. H⁺ translocation by weak acid uncouplers is independent of H+ electrochemical gradient. J Bioenerg Biomembr 2017; 49(5): 391-7. [PMID: 28900787 DOI: 10.1007/s10863-017-9724-x]

[182] Black PA, Warren RM, Louw GE, Van Helden PD, Victor TC, et al. Energy metabolism and drug efflux in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2014; 58(5): 2491-503. [PMID: 24614376 DOI: 10.1128/AAC.02293-13]

[183] Umar F, Hatta M, Husain DR, Bahar B, Bukhari A, et al. Verapamil as an efflux inhibitor against drug resistant Mycobacterium tuberculosis: a review. Sys Rev Pharm 2019; 10(1): S43-8. [DOI: 10.5530/srp.2019.1s.22]

[184] Remm S, Earp JC, Dick T, Dartois V, Seeger MA. Critical discussion on drug efflux in Mycobacterium tuberculosis . FEMS Microbiol Rev 2022; 46(1): fuab050. [PMID: 34637511 DOI: 10.1093/femsre/fuab050]

[185] Li G, Zhang J, Li C, Guo Q, Jiang Y, et al. Antimycobacterial activity of five efflux pump inhibitors against Mycobacterium tuberculosis clinical isolates. J Antibiot (Tokyo) 2016; 69(3): 173-5. [PMID: 26464012 DOI: 10.1038/ja.2015.101]

[186] Gupta S, Cohen KA, Winglee K, Maiga M, Diarra B, et al. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2014; 58(1): 574-6. [PMID: 24126586 DOI: 10.1128/AAC.01462-13]

[187] Xu J, Tasneen R, Peloquin CA, Almeida DV, Li SY, et al. Verapamil increases the bioavailability and efficacy of bedaquiline but not clofazimine in a murine model of tuberculosis. Antimicrob Agents Chemother 2018; 62(1): e01692-17. [PMID: 29038265 DOI: 10.1128/AAC.01692-17]

[188] Jang J, Kim R, Woo M, Jeong J, Park DE, et al. Efflux attenuates the antibacterial activity of Q203 in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2017; 61(7): e02637-16. [PMID: 28416541 DOI: 10.1128/AAC.02637-16]

[189] Gupta S, Tyagi S, Bishaia WR. Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother 2015; 59(1): 673-6. [PMID: 25331694 DOI: 10.1128/AAC.04019-14]

[190] Caleffi-Ferracioli KR, Cardoso RF, De Souza JVP, Murase LS, Canezin PH, et al. Modulatory effects of verapamil in rifampicin activity against Mycobacterium tuberculosis . Future Microbiol 2019; 14(3): 185-94. [PMID: 30648892 DOI: 10.2217/fmb-2018-0277]

[191] Singh K, Kumar M, Pavadai E, Naran K, Warner DF, et al. Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c. Bioorg Med Chem Lett 2014; 24(14): 2985-90. [PMID: 24894561 DOI: 10.1016/j.bmcl.2014.05.022]

[192] Adams KN, Szumowski JD, Ramakrishnan L. Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs. J Infect Dis 2014; 210(3): 456-66. [PMID: 24532601 DOI: 10.1093/infdis/jiu095]

[193] Lake MA, Adams KN, Nie F, Fowler E, Verma AK, et al. The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance. Proc Natl Acad Sci USA 2023; 120(7): e2215512120. [PMID: 36763530 DOI: 10.1073/pnas.2215512120]

[194] Garrison AT, Abouelhassan Y, Kallifidas D, Bai F, Ukhanova M, et al. Halogenated phenazines that potently eradicate biofilms, MRSA persister cells in non-biofilm cultures, and Mycobacterium tuberculosis . Angew Chem Int Ed Engl 2015; 127(49): 15032-6. [PMID: 26480852 DOI: 10.1002/anie.201508155]

[195] Kristiansen JE, Dastidar SG, Palchoudhuri S, Roy DS, Das S, et al. Phenothiazines as a solution for multidrug resistant tuberculosis: From the origin to present. Int Microbiol 2015; 18(1): 1-12. [PMID: 26415662 DOI: 10.2436/20.1501.01.229]

[196] Kumar M, Singh K, Naran K, Hamzabegovic F, Hoft DF, et al. Design, synthesis, and evaluation of novel hybrid efflux pump inhibitors for use against Mycobacterium tuberculosis . ACS Infect Dis 2016; 2: 714-25. [PMID: 27737555 DOI: 10.1021/acsinfecdis.6b00111]

[197] Vibe CB, Fenaroli F, Pires D, Wilson SR, Bogoeva V, et al. Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish. Nanotoxicology 2016; 10(6): 680-8. [PMID: 26573343 DOI: 10.3109/17435390.2015.1107146]

[198] Ruth MM, Pennings LJ, Koeken VACM, Schildkraut JA, Hashemi A, et al. Thioridazine is an efflux pump inhibitor in Mycobacterium avium complex but of limited clinical relevance. Antimicrob Agents Chemother 2020; 64(7): e00181. [PMID: 32312774 DOI: 10.1128/AAC.00181-20]

[199] Machado D, Pires D, Perdigão J, Couto I, Portugal I, 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. [PMID: 26919135 DOI: 10.1371/journal.pone.0149326]

[200] Pieroni M, Machado D, Azzali E, Santos Costa S, Couto I, et al. Rational design and synthesis of thioridazine analogues as enhancers of the antituberculosis therapy. J Med Chem 2015; 58(15): 5842-53. [PMID: 26197353 DOI: 10.1021/acs.jmedchem.5b00428]

[201] Grossman TH, Shoen CM, Jones SM, Jones PL, Cynamon MH, et al. The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents. Antimicrob Agents Chemother 2015; 59(3): 1534-41. [PMID: 25534740 DOI: 10.1128/AAC.04271-14]

[202] Mudde SE, Schildkraut JA, Ammerman NC, de Vogel CP, de Steenwinkel JEM, et al. Unraveling antibiotic resistance mechanisms in Mycobacterium abscessus: the potential role of efflux pumps. J Glob Antimicrob Resist 2022; 31: 345-52. [PMID: 36347496 DOI: 10.1016/j.jgar.2022.10.015]

[203] Martin A, Bouyakoub Y, Soumillion K, Mantu EON, Colmant A, et al. Targeting bedaquiline mycobacterial efflux pump to potentially enhance therapy in Mycobacterium abscessus . Int J Mycobacteriol 2020; 9(1): 71-5. [PMID: 32474492 DOI: 10.4103/ijmy.ijmy_181_19]

[204] Menichini M, Lari N, Rindi L. Effect of efflux pump inhibitors on the susceptibility of Mycobacterium avium complex to clarithromycin. J Antibiot (Tokyo) 2020; 73(2): 128-32. [PMID: 31624335 DOI: 10.1038/s41429-019-0245-1]

[205] Danquah CA, Kakagianni E, Khondkar P, Maitra A, Rahman M, et al. Analogues of disulfides from allium stipitatum demonstrate potent anti-tubercular activities through drug efflux pump and biofilm inhibition. Sci Rep 2018; 8(1): 1150. [PMID: 29348586 DOI: 10.1038/s41598-017-18948-w]

[206] Halicki PCB, Vianna JS, Zanatta N, de Andrade VP, de Oliveira M, et al. 2,2,2-trifluoro-1-(1,4,5,6-tetrahydropyridin-3-yl)ethanone derivative as efflux pump inhibitor in Mycobacterium tuberculosis . Bioorg Med Chem Lett 2021; 42: 128088. [PMID: 33964440 DOI: 10.1016/j.bmcl.2021.128088]

[207] Cannalire R, Machado D, Felicetti T, Santos Costa S, Massari S, 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: 321-30. [PMID: 28964936 DOI: 10.1016/j.ejmech.2017.09.014]

[208] Felicetti T, Machado D, Cannalire R, Astolfi A, Massari S, et al. Modifications on C6 and C7 positions of 3-phenylquinolone efflux pump inhibitors led to potent and safe antimycobacterial treatment adjuvants. ACS Infect Dis 2019; 5(6): 982-1000. [PMID: 30907573 DOI: 10.1021/acsinfecdis.9b00041]

[209] Sen T, Neog K, Sarma S, Manna P, Deka Boruah HP, et al. Efflux pump inhibition by 11H-pyrido[2,1-b]quinazolin-11-one analogues in mycobacteria. Bioorg Med Chem 2018; 26(17): 4942-51. [PMID: 30190182 DOI: 10.1016/j.bmc.2018.08.034]

[210] Shyam M, Verma H, Bhattacharje G, Mukherjee P, Singh S, et al. Mycobactin analogues with excellent pharmacokinetic profile demonstrate potent antitubercular specific activity and exceptional efflux pump inhibition. J Med Chem 2022; 65(1): 234-56. [DOI: 10.1021/acs.jmedchem.1c01349]

[211] Felicetti T, Cannalire R, Pietrella D, Latacz G, Lubelska A, et al. 2-Phenylquinoline S. aureus NorA efflux pump inhibitors: evaluation of the importance of methoxy group introduction. J Med Chem 2018; 61(17): 7827-48. [PMID: 30067360 DOI: 10.1021/acs.jmedchem.8b00791]

[212] Machado D, Cannalire R, Santos Costa S, Manfroni G, Tabarrini O, et al. Boosting effect of 2-Phenylquinoline efflux inhibitors in combination with macrolides against Mycobacterium smegmatis and Mycobacterium avium . ACS Infect Dis 2015; 1(12): 593-603. [PMID: 27623057 DOI: 10.1021/acsinfecdis.5b00052]

[213] Corona P, Ibba R, Piras S, Molicotti P, Bua A, et al. Quinoxaline-based efflux pump inhibitors restore drug susceptibility in drug-resistant nontuberculous mycobacteria. Arch Pharm (Weinheim) 2022; 355(8): e2100492. [PMID: 35532283 DOI: 10.1002/ardp.202100492]

[214] Duran M, Araiza A, Surani SR, Vakil A, Varon J. Pulmonary infection caused by Mycobacterium terrae: a case report and literature review. Cureus 2019; 11(11): 1-9. [PMID: 31890427 DOI: 10.7759/cureus.6228]

[215] Little JS, Dedrick RM, Freeman KG, Cristinziano M, Smith BE, et al. Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection. Nat Commun 2022; 13(1): 2313. [PMID: 35504908 DOI: 10.1038/s41467-022-29689-4]

[216] Pinto-Gouveia M, Gameiro A, Ramos L, Cardoso JC, Brites MM, et al. Mycobacterium chelonae is an ubiquitous atypical mycobacterium. Case Rep Dermatol 2015; 7(2): 207-11. [PMID: 26351432 DOI: 10.1159/000438898]

[217] Saffo Z, Ognjan A. Mycobacterium smegmatis infection of a prosthetic total knee arthroplasty. IDCases 2016; 5: 80-2. [PMID: 27516972 DOI: 10.1016/j.idcr.2016.07.007]

[218] Koul A, Arnoult E, Lounis N, Guillemont J, Andries K. The challenge of new drug discovery for tuberculosis. Nature 2011; 469(7331): 483-90. [PMID: 21270886 DOI: 10.1038/nature09657]

[219] Protopopova M, Hanrahan C, Nikonenko B, Samala R, Chen P, et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother 2005; 56(5): 968-74. [PMID: 16172107 DOI: 10.1093/jac/dki319]

[220] Foss MH, Pou S, Davidson PM, Dunaj JL, Winter RW, et al. Diphenylether-modified 1,2-diamines with improved drug properties for development against Mycobacterium tuberculosis . ACS Infect Dis 2016; 2(7): 500-8. [PMID: 27626102 DOI: 10.1021/acsinfecdis.6b00052]

[221] Tahlan K, Wilson R, Kastrinsky DB, Arora K, Nair V, et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis . Antimicrob Agents Chemother 2012; 56(4): 1797-809. [PMID: 22252828 DOI: 10.1128/AAC.05708-11]

[222] Hoagland DT, Liu J, Lee RB, Lee RE. New agents for the treatment of drug-resistant Mycobacterium tuberculosis . Adv Drug Deliv Rev 2016; 102: 55-72. [PMID: 27151308 DOI: 10.1016/j.addr.2016.04.026]

[223] Riccardi G, Pasca MR, Chiarelli LR, Manina G, Mattevi A, et al. The DprE1 enzyme, one of the most vulnerable targets of Mycobacterium tuberculosis . Appl Microbiol Biotechnol 2013; 97(20): 8841-8. [PMID: 24037308 DOI: 10.1007/s00253-013-5218-x]

[224] Chikhale RV, Barmade MA, Murumkar PR, Yadav MR. Overview of the development of DprE1 inhibitors for combating the menace of tuberculosis. J Med Chem 2018; 61(19): 8563-93. [PMID: 29851474 DOI: 10.1021/acs.jmedchem.8b00281]

[225] Hariguchi H, Chen X, Hayashi Y, Kawano Y, Fujiwara M, et al. OPC-167832, a novel carbostyril derivative with potent. Antimicrob Agents Chemother 2020; 64(6): 1-13. [DOI: 10.1128/AAC.02020-19]

[226] Pomar V, Martínez JA. MESA: Nuevas pautas de tratamiento en TB. Analysis of pooled delamanid clinical trials data and new Otsuka TB product developments. Rev Enf Emerg 2018; 17(3): 116-21.

[227] Butler MS, Paterson DL. Antibiotics in the clinical pipeline in October 2019. J Antibiot 2020; 73(6): 329-64. [PMID: 32152527 DOI: 10.1038/s41429-020-0291-8]

[228] Shirude PS, Shandil R, Sadler C, Naik M, Hosagrahara V, et al. Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are Efficacious in vivo. J Med Chem 2013; 56: 9701-8. [PMID: 24215368 DOI: 10.1021/jm401382v]

[229] Shetye GS, Franzblau SG, Cho S. New tuberculosis drug targets, their inhibitors, and potential therapeutic impact. Transl Res 2020; 220: 68-97. [PMID: 32275897 DOI: 10.1016/j.trsl.2020.03.007]

[230] Kempf DJ, Marsh KC. Assembling pharma resources to tackle diseases of underserved populations. ACS Med Chem Lett 2020; 11(6): 1094-100. [PMID: 32550987 DOI: 10.1021/acsmedchemlett.0c00051]

[231] Andries K, Verhasselt P, Guillemont J, Göhlmann HW, Neefs JM, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis . Science 2005; 307(5707): 223-7. [PMID: 15591164 DOI: 10.1126/science.1106753]

[232] Cohen J. Infectious disease. Approval of novel TB drug celebrated —— with restraint. Science 2013; 339(6116): 130. [PMID: 23307714 DOI: 10.1126/science.339.6116.130]

[233] Sutherland HS, Tong AST, Choi PJ, Blaser A, Conole D, et al. 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem 2019; 27(7): 1292-307. [PMID: 30803745 DOI: 10.1016/j.bmc.2019.02.026]

[234] Sarathy JP, Ragunathan P, Shin J, Cooper CB, Upton AM, et al. TBAJ-876 retains bedaquiline’s activity against subunits c and ε of Mycobacterium tuberculosis F-ATP synthase. Antimicrob Agents Chemother 2019; 63(10): e01191-19. [PMID: 31358589 DOI: 10.1128/AAC.01191-19]

[235] O’Donnell MR, Padayatchi N, Metcalfe JZ. Elucidating the role of clofazimine for the treatment of tuberculosis. Int J Tuberc Lung Dis 2016; 20(12): S52-7. [PMID: 28240574 DOI: 10.5588/ijtld.16.0073]

[236] Dalcolmo M, Gayoso R, Sotgiu G, D’Ambrosio L, Rocha JL, et al. Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: a nationwide report from Brazil. Eur Respir J 2017; 49(3): 1602445. [PMID: 28331044 DOI: 10.1183/13993003.02445-2016]

[237] Diacon AH, Dawson R, Von Groote-Bidlingmaier F, Symons G, Venter A, et al. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med 2015; 191(8): 943-53. [PMID: 25622149 DOI: 10.1164/rccm.201410-1801OC]

[238] Dey T, Brigden G, Cox H, Shubber Z, Cooke G, et al. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother 2013; 68(2): 284-93. [PMID: 23054996 DOI: 10.1093/jac/dks389]

[239] Lechartier B, Cole ST. Mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis . Antimicrob Agents Chemother 2015; 59(8): 4457-63. [PMID: 25987624 DOI: 10.1128/AAC.00395-15]

[240] Cholo MC, Mothiba MT, Fourie B, Anderson R. Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline. J Antimicrob Chemother 2017; 72(2): 338-53. [PMID: 27798208 DOI: 10.1093/jac/dkw426]

[241] Lu Y, Zheng M, Wang B, Fu L, Zhao W, et al. Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation. Antimicrob Agents Chemother 2011; 55(11): 5185-93. [PMID: 21844321 DOI: 10.1128/AAC.00699-11]

[242] Xu J, Wang B, Fu L, Zhu H, Guo S, et al. In vitro and in vivo activities of the riminophenazine TBI-166 against Mycobacterium tuberculosis . Antimicrob Agents Chemother 2019; 63(5): e02155-18. [PMID: 30782992 DOI: 10.1128/AAC.02155-18]

[243] Pethe K, Bifani P, Jang J, Kang S, Park S, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 2013; 19(9): 1157-60. [PMID: 23913123 DOI: 10.1038/nm.3262]

[244] Scherr N, Bieri R, Thomas SS, Chauffour A, Kalia NP, et al. Targeting the Mycobacterium ulcerans cytochrome bc₁:aa₃ for the treatment of Buruli ulcer. Nat Commun 2018; 9(1): 5370. [PMID: 30560872 DOI: 10.1038/s41467-018-07804-8]

[245] Chauffour A, Robert J, Veziris N, Aubry A, Pethe K, et al. Q203 containing fully intermittent oral regimens exhibited high sterilizing activity against Mycobacterium ulcerans in mice. bioRxiv 2019; 813253. [DOI: 10.1101/813253]

[246] Almeida DV, Converse PJ, Omansen TF, Tyagi S, Tasneen R, et al. Telacebec for ultrashort treatment of Buruli ulcer in a mouse model. Antimicrob Agents Chemother 2020; 64(6): e00259-20. [PMID: 32205344 DOI: 10.1128/AAC.00259-20]

[247] Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006; 3(11): 2131-44. [PMID: 17132069 DOI: 10.1371/journal.pmed.0030466]

[248] van den Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE . New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development. Antimicrob Agents Chemother 2009; 53(3): 849-62. [PMID: 19075046 DOI: 10.1128/AAC.00749-08]

[249] Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, et al. PA-824 kills nonreplicating mycobacterium tuberculosis by intracellular NO release. Science 2008; 322(5906): 1392-5. [PMID: 19039139 DOI: 10.1126/science.1164571]

[250] Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405(6789): 962-6. [PMID: 10879539 DOI: 10.1038/35016103]

[251] Aslam S, Musher DM. Nitazoxanide: clinical studies of a broad-spectrum anti-infective agent. Future Microbiol 2007; 2(6): 583-90. [PMID: 18041899 DOI: 10.2217/17460913.2.6.583]

[252] Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, et al. Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis c virus replication. J Med Chem 2011; 54(24): 8670-80. [PMID: 22059983 DOI: 10.1021/jm201264t]

[253] de Carvalho LPS, Lin G, Jiang X, Nathan C. Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance. J Med Chem 2009; 52(19): 5789-92. [PMID: 19736929 DOI: 10.1021/jm9010719]

[254] de Carvalho LPS, Darby CM, Rhee KY, Nathan C. Nitazoxanide disrupts membrane potential and intrabacterial pH homeostasis of Mycobacterium tuberculosis . ACS Med Chem Lett 2011; 2(11): 849-54. [PMID: 22096616 DOI: 10.1021/ml200157f]

[255] Singh KV, Coque TM, Murray BE. In vitro activity of the trinem sanfetrinem (GV104326) against gram-positive organisms. Antimicrob Agents Chemother 1996; 40(9): 2142-6. [PMID: 8878596 DOI: 10.1128/AAC.40.9.2142]

[256] El-Gamal MI, Brahim I, Hisham N, Aladdin R, Mohammed H, et al. Recent updates of carbapenem antibiotics. Eur J Med Chem 2017; 131: 185-95. [PMID: 28324783 DOI: 10.1016/j.ejmech.2017.03.022]

[257] Vilchèze C. Mycobacterial cell wall: a source of successful targets for old and new drugs. Appl Sci 2020; 10(7): 2278. [DOI: 10.3390/app10072278]

[258] Chopra I. Research and development of antibacterial agents. Curr Opin Microbiol 1998; 1(5): 495-501. [PMID: 10066523 DOI: 10.1016/s1369-5274(98)80080-5]

[259] Tripathi RP, Tewari N, Dwivedi N, Tiwari VK. Fighting tuberculosis: an old disease with new challenges. Med Res Rev 2005; 25(1): 93-131. [PMID: 15389729 DOI: 10.1002/med.20017]

[260] Rivers EC, Mancera RL. New anti-tuberculosis drugs with novel mechanisms of action. Curr Med Chem 2008; 15(19): 1956-67. [PMID: 18691051 DOI: 10.2174/092986708785132906]

[261] Leach KL, Brickner SJ, Noe MC, Miller PF. Linezolid, the first oxazolidinone antibacterial agent. Ann N Y Acad Sci 2011; 1222(1): 49-54. [PMID: 21434942 DOI: 10.1111/j.1749-6632.2011.05962.x]

[262] Zhu T, Friedrich SO, Diacon A, Wallis RS. Population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (PNU-100480) and its major metabolite against intracellular Mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis. Antimicrob Agents Chemother 2014; 58(6): 3306-11. [PMID: 24687496 DOI: 10.1128/AAC.01920-13]

[263] Jeong JW, Jung SJ, Lee HH, Kim YZ, Park TK, et al. In vitro and in vivo activities of LCB01-0371, a new oxazolidinone. Antimicrob Agents Chemother 2010; 54(12): 5359-62. [PMID: 20855730 DOI: 10.1128/AAC.00723-10]

[264] Cho YL, Jang J. Development of delpazolid for the treatment of tuberculosis. Appl Sci 2020; 10(7): 2211. [DOI: 10.3390/app10072211]

[265] Zong Z, Jing W, Shi J, Wen S, Zhang T, et al. Comparison of in vitro activity and MIC distributions between the novel oxazolidinone delpazolid and linezolid against multidrug-resistant and extensively drug-resistant mycobacterium tuberculosis in China. Antimicrob Agents Chemother 2018; 62(8): e00165-18. [PMID: 29844043 DOI: 10.1128/AAC.00165-18]

[266] Mdluli K, Cooper C, Yang T, Lotlikar M, Betoudji F, et al. TBI-223: a safer oxazolidinone in pre-clinical development for tuberculosis. In Proceedings of the ASM Microbe 2017, 1-5 June 2017; New Orleans, LA, USA; 2017. Session 335-AAID-Sunday-50.

[267] Lociuro S. BioVersys receives QIDP designation from the U.S. FDA for the development of a fixed combination of BVL-GSK098 and ETH. BVL-GSK098 is being developed for the treatment of multi-drug resistant. Press Release BioVersys. 2020; 1-3.

[268] Rosenthal IM, Zhang M, Williams KN, Peloquin CA, Tyagi S, et al. Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med 2007; 4(12): e344. [PMID: 18092886 DOI: 10.1371/journal.pmed.0040344]

[269] Faustino C, Andrade JM, Ferreira IM, Almeida JF, Rijo P. Lead molecules from natural products: insight into tubercular targets . Studies in Natural Products Chemistry; 2020; 65. pp. 41-84.

[270] Igarashi M, Ishizaki Y, Takahashi Y. New antituberculous drugs derived from natural products: current perspectives and issues in antituberculous drug development. J Antibiot 2018; 71(1): 15-25. [DOI: 10.1038/ja.2017.126]

[271] Grosset JH, Singer TG, Bishai WR. New drugs for the treatment of tuberculosis: hope and reality. Int J Tuberc Lung Dis 2012; 16(8): 1005-14. [PMID: 22762423 DOI: 10.5588/ijtld.12.0277]

[272] Madhura DB, Liu J, Meibohm B, Lee RE . Phase II metabolic pathways of spectinamide antitubercular agents: a comparative study of the reactivity of 4-substituted pyridines to glutathione conjugation. Medchemcomm 2016; 7(1): 114-7. [PMID: 27042286 DOI: 10.1039/C5MD00349K]

[273] Lee RE, Hurdle JG, Liu J, Bruhn DF, Matt T, et al. Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux. Nat Med 2014; 20(2): 152-8. [PMID: 24464186 DOI: 10.1038/nm.3458]

[274] Bruhn DF, Scherman MS, Liu J, Scherbakov D, Meibohm B, et al. In vitro and in vivo evaluation of synergism between anti-tubercular spectinamides and non-classical tuberculosis antibiotics. Sci Rep 2015; 5: 13985. [DOI: 10.1038/srep13985]

[275] Lee SFK, Laughon BE, McHugh TD, Lipman M. New drugs to treat difficult tuberculous and nontuberculous mycobacterial pulmonary disease. Curr Opin Pulm Med 2019; 25(3): 271-80. [PMID: 30865034 DOI: 10.1097/MCP.0000000000000570]

[276] Gygli SM, Borrell S, Trauner A, Gagneux S. Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiology Reviews. Oxford University Press; 2017; 41. p. 354-73.

[277] Blondiaux N, Moune M, Desroses M, Frita R, Flipo M, et al. Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science 2017; 1211: 1206-11. [PMID: 28302858 DOI: 10.1126/science.aag1006]

[278] Hoehl S, Rabenau H, Berger A, Kortenbusch M, Cinatl J, et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China. N Engl J Med 2020; 382(13): 1278-80. [PMID: 32069388 DOI: 10.1056/NEJMc2001899]

[279] Pasca MR, Guglierame P, Arcesi F, Bellinzoni M, De Rossi E, et al. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2004; 48(8): 3175- 8. [PMID: 15273144 DOI: 10.1128/AAC.48.8.3175-3178.2004]

[280] Khosravi AD, Sirous M, Absalan Z, Tabandeh MR, Savari M. 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: 3437-44. [PMID: 31807034 DOI: 10.2147/IDR.S221823]

[281] Schmalstieg AM, Srivastava S, Belkaya S, Deshpande D, Meek C, 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): 4806-15. [PMID: 22751536 DOI: 10.1128/AAC.05546-11]

[282] Oh TS, Kim YJ, Kang HY, Kim CK, Cho SY, et al. RNA expression analysis of efflux pump genes in clinical isolates of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis in South Korea. Infect Genet Evol 2017; 49: 111-5. [PMID: 28062386 DOI: 10.1016/j.meegid.2017.01.002]

[283] Takiff HE, Cimino M, Musso MC, Weisbrod T, Martinez R, et al. Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis . Proc Natl Acad Sci U S A 1996; 93(1): 362-6. [PMID: 8552639 DOI: 10.1073/pnas.93.1.362]

[284] Pasca MR, Guglierame P, De Rossi E, Zara F, Riccardi G. mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis . Antimicrob Agents Chemother 2005; 49(11): 4775-7. [PMID: 16251328 DOI: 10.1128/AAC.49.11.4775-4777.2005]