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Rifamycin antibiotics and the mechanisms of their failure

The Journal of Antibiotics volume 74, pages 786–798 (2021)Cite this article

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Abstract

Rifamycins are a class of antibiotics that were first discovered in 1957 and are known for their use in treating tuberculosis (TB). Rifamycins exhibit bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting RNA polymerase (RNAP); however, resistance is prevalent and the mechanisms range from primary target modification and antibiotic inactivation to cytoplasmic exclusion. Further, phenotypic resistance, in which only a subpopulation of bacteria grow in concentrations exceeding their minimum inhibitory concentration, and tolerance, which is characterized by reduced rates of bacterial cell death, have been identified as additional causes of rifamycin failure. Here we summarize current understanding and recent developments regarding this critical antibiotic class.

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References

  1. Rinehart KL. Antibiotics with ansa rings. Acc Chem Res. 1972;5:57–64.

    Article  CAS  Google Scholar 

  2. Rothstein DM. Rifamycins, alone and in combination. Cold Spring Harb Perspect Med. 2016;6:a027011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Corpe RF, Sanchez ES. Rifampin in initial treatment of advanced pulmonary tuberculosis. Chest. 1972;61:564–73.

    Article  CAS  PubMed  Google Scholar 

  4. Munsiff SS, Kambili C, Ahuja SD. Rifapentine for the treatment of pulmonary tuberculosis. Clin Infect Dis. 2006;43:1468–75.

    Article  CAS  PubMed  Google Scholar 

  5. Newman R, Doster B, Murray FJ, Ferebee S. Rifampin in initial treatment of pulmonary tuberculosis. A U.S. Public Health Service tuberculosis therapy trial. Am Rev Respir Dis. 1971;103:461–76.

    CAS  PubMed  Google Scholar 

  6. Van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis. 2011;52:e194–9.

    Article  PubMed  CAS  Google Scholar 

  7. Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56:e1–25.

    Article  PubMed  Google Scholar 

  8. Zimmerli W, Sendi P. Role of Rifampin against Staphylococcal biofilm infections in vitro, in animal models, and in orthopedic-device-related infections. Antimicrob Agents Chemother. 2019;63:e01746–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baronti A, Lukinovich N. A pilot trial of rifampicin in tuberculosis. Tubercle 1968;49:180–6.

    Article  CAS  PubMed  Google Scholar 

  10. Hyde L. Rifampin in the treatment of pulmonary tuberculosis. Calif Med. 1972;117:18–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Vall-Spinosa A, Lester W, Moulding T, Davidson PT, McClatchy JK. Rifampin in the treatment of drug-resistant Mycobacterium tuberculosis infections. N Engl J Med. 1970;283:616–21.

    Article  CAS  PubMed  Google Scholar 

  12. CDC. Tuberculosis data and statistics. 2019. https://www.cdc.gov/tb/statistics/reports/2019/default.htm.

  13. Dickinson JM, Mitchison DA. In vitro activity of new rifamycins against rifampicin-resistant M. tuberculosis and MAIS-complex mycobacteria. Tubercle. 1987;68:177–82.

    Article  CAS  PubMed  Google Scholar 

  14. Tam CM, Chan SL, Lam CW, Leung CC, Kam KM, Morris JS, et al. Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis. Initial report. Am J Respir Crit Care Med. 1998;157:1726–33.

    Article  CAS  PubMed  Google Scholar 

  15. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet. 1999;353:1843–7.

    Article  CAS  PubMed  Google Scholar 

  16. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis. 2006;6:710–25.

    Article  PubMed  Google Scholar 

  17. WHO. Global tuberculosis report 2020. WHO institutional repository for information sharing. 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf.

  18. Sharling L, Marks SM, Goodman M, Chorba T, Mase S. Rifampin-resistant Tuberculosis in the United States, 1998-2014. Clin Infect Dis. 2020;70:1596–605.

    Article  CAS  PubMed  Google Scholar 

  19. Kaur R, Jindal N, Arora S, Kataria S. Epidemiology of rifampicin resistant tuberculosis and common mutations in rpoB gene of Mycobacterium tuberculosis: a retrospective study from six districts of Punjab (India) using Xpert MTB/RIF assay. J Lab Physicians. 2016;8:96–100.

    Article  PubMed  PubMed Central  Google Scholar 

  20. WHO. WHO releases the 2019 AWaRe Classification Antibiotics. (April 20, 2021). 2019. https://www.who.int/publications/i/item/WHOEMPIAU2019.11.

  21. Matteelli A, Rendon A, Tiberi S, Al-Abri S, Voniatis C, Carvalho A, et al. Tuberculosis elimination: where are we now? Eur Respir Rev. 2018;27:180035.

    Article  PubMed  Google Scholar 

  22. Sensi P. History of the development of Rifampin. Rev Infect Dis. 1983;5:S402–6.

    Article  CAS  PubMed  Google Scholar 

  23. Margalith P, Beretta G. Rifomycin. XI. taxonomic study on Streptomyces mediterranei nov. sp. Mycopathol Mycol Appl. 1960;13:321–30.

    Article  Google Scholar 

  24. Lester W. Rifampin: a semisynthetic derivative of rifamycin–a prototype for the future. Annu Rev Microbiol. 1972;26:85–102.

    Article  CAS  PubMed  Google Scholar 

  25. Margalith P, Pagani H. Rifomycin. XIV. Production of rifomycin B. Appl Microbiol. 1961;9:325–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sensi P, Margalith P. Antibiotic rifamycin b and method of production—US3150046A. 1964. https://patentimages.storage.googleapis.com/ae/cd/00/32617eb19a2b76/US3150046.pdf.

  27. Sensi P, Timbal MT, Maffii G, Rifomycin IX. Two new antibiotics of rifomycin family: rifomycin S and rifomycin SV. Preliminary report. Experientia. 1960;16:412.

    Article  CAS  PubMed  Google Scholar 

  28. Verbist L, Gyselen A. Antituberculous activity of rifampin in vitro and in vivo and the concentrations attained in human blood. Am Rev Respir Dis. 1968;98:923–32.

    CAS  PubMed  Google Scholar 

  29. Prelog V. Constitution of rifamycins. Pure Appl Chem. 1963;7:551–64.

    Article  CAS  Google Scholar 

  30. Riva MA. From milk to rifampicin and back again: history of failures and successes in the treatment for tuberculosis. J Antibiot. 2014;67:661–5.

    Article  CAS  Google Scholar 

  31. Bullock WE. Rifampin in the treatment of leprosy. Rev Infect Dis. 1983;5:S606–13.

    Article  PubMed  Google Scholar 

  32. Bretonnière C, Jozwiak M, Girault C, Beuret P, Trouillet JL, Anguel N, et al. Rifampin use in acute community-acquired meningitis in intensive care units: the French retrospective cohort ACAM-ICU study. Crit Care. 2015;19:303.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Greimel F, Scheuerer C, Gessner A, Simon M, Kalteis T, Grifka J, et al. Efficacy of antibiotic treatment of implant-associated Staphylococcus aureus infections with moxifloxacin, flucloxacillin, rifampin, and combination therapy: an animal study. Drug Des Dev Ther. 2017;11:1729–36.

    Article  CAS  Google Scholar 

  34. Sharma L, Losier A, Tolbert T, Dela Cruz CS, Marion CR. Pneumonia updates on legionella, chlamydophila, and mycoplasma pneumonia. Clin Chest Med. 2017;38:45–58.

    Article  PubMed  Google Scholar 

  35. Karlsen ØE, Borgen P, Bragnes B, Figved W, Grøgaard B, Rydinge J, et al. Rifampin combination therapy in staphylococcal prosthetic joint infections: a randomized controlled trial. J Orthop Surg Res. 2020;15:365.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Renz N, Trampuz A, Zimmerli W. Controversy about the role of rifampin in biofilm infections: is it justified? Antibiotics. 2021;10:165.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Nguyen L. Antibiotic resistance mechanisms in M. tuberculosis: an update. Arch Toxicol. 2016;90:1585–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hong KS, Kim JS. Rifaximin for the treatment of acute infectious diarrhea. Therapeutic Adv Gastroenterol. 2011;4:227–35.

    Article  CAS  Google Scholar 

  39. Huang JS, Jiang ZD, Garey KW, Lasco T, DuPont HL. Use of rifamycin drugs and development of infection by rifamycin-resistant strains of Clostridium difficile. Antimicrob Agents Chemother. 2013;57:2690–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Floss HG, Yu T-W. Rifamycin mode of action, resistance, and biosynthesis. Chem Rev. 2005;105:621–32.

    Article  CAS  PubMed  Google Scholar 

  41. Ghisalba O, Nüesch J. A genetic approach to the biosynthesis of the rifamycin-chromophore in Nocardia mediterranei. IV. Identification of 3-amino-5-hydroxybenzoic acid as a direct precursor of the seven-carbon amino starter-unit. J Antibiot. 1981;34:64–71.

    Article  CAS  Google Scholar 

  42. Gygax D, Ghisalba O, Treichler H, Nüesch J. Study to the biosynthesis of the rifamycin-chromophore in Nocardia mediterranei. J Antibiot. 1990;43:324–6.

    Article  CAS  Google Scholar 

  43. Floss HG, Yu TW, Arakawa K. The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC7N units in ansamycin and mitomycin antibiotics: a review. J Antibiot. 2011;64:35–44.

    Article  CAS  Google Scholar 

  44. Tang L, Yoon YJ, Choi C-Y, Hutchinson CR. Characterization of the enzymatic domains in the modular polyketide synthase involved in rifamycin B biosynthesis by Amycolatopsis mediterranei. Gene. 1998;216:255–65.

    Article  CAS  PubMed  Google Scholar 

  45. August PR, Tang L, Yoon YJ, Ning S, Müller R, Yu TW, et al. Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. Chem Biol. 1998;5:69–79.

    Article  CAS  PubMed  Google Scholar 

  46. Admiraal SJ, Walsh CT, Khosla C. The loading module of rifamycin synthetase is an adenylation–thiolation didomain with substrate tolerance for substituted benzoates. Biochemistry. 2001;40:6116–23.

    Article  CAS  PubMed  Google Scholar 

  47. Yu TW, Shen Y, Doi-Katayama Y, Tang L, Park C, Moore BS, et al. Direct evidence that the rifamycin polyketide synthase assembles polyketide chains processively. Proc Natl Acad Sci USA. 1999;96:9051.LP–6.

    Article  Google Scholar 

  48. Xu J, Wan E, Kim C-J, Floss HG, Mahmud T. Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699. Microbiology. 2005;151:2515–28.

    Article  CAS  PubMed  Google Scholar 

  49. Stratmann A, Schupp T, Toupet C, Schilling W, Oberer L, Traber R. New insights into rifamycin B biosynthesis: isolation of proansamycin B and 34a-Deoxy-rifamycin W as early macrocyclic intermediates indicating two separated biosynthetic pathways. J Antibiot. 2002;55:396–406.

    Article  CAS  Google Scholar 

  50. White RJ, Martinelli E, Lancini G. Ansamycin Biogenesis: Studies on a Novel Rifamycin Isolated from a Mutant Strain of Nocardia mediterranei. Proc Natl Acad Sci USA. 1974;71:3260–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ye F, Shi Y, Zhao S, Li Z, Wang H, Lu C, et al. 8-Deoxy-rifamycin derivatives from Amycolatopsis mediterranei S699 ΔrifT strain. Biomolecules. 2020;10:1265.

    Article  CAS  PubMed Central  Google Scholar 

  52. Xiong Y, Wu X, Mahmud T. A homologue of the Mycobacterium tuberculosis PapA5 Protein, Rif-Orf20, Is an acetyltransferase involved in the biosynthesis of antitubercular drug rifamycin B by Amycolatopsis mediterranei S699. ChemBioChem. 2005;6:834–7.

    Article  CAS  PubMed  Google Scholar 

  53. Xu J, Mahmud T, Floss HG. Isolation and characterization of 27-O-demethylrifamycin SV methyltransferase provides new insights into the post-PKS modification steps during the biosynthesis of the antitubercular drug rifamycin B by Amycolatopsis mediterranei S699. Arch Biochem Biophys. 2003;411:277–88.

    Article  CAS  PubMed  Google Scholar 

  54. Yuan H, Zhao W, Zhong Y, Wang J, Qin Z, Ding X, et al. Two genes, rif15 and rif16, of the rifamycin biosynthetic gene cluster in Amycolatopsis mediterranei likely encode a transketolase and a P450 monooxygenase, respectively, both essential for the conversion of rifamycin SV into B. Acta Biochim Biophys Sin. 2011;43:948–56.

    Article  CAS  PubMed  Google Scholar 

  55. Qi F, Lei C, Li F, Zhang X, Wang J, Zhang W, et al. Deciphering the late steps of rifamycin biosynthesis. Nat Commun. 2018;9:2342.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Bujnowski K, Synoradzki L, Darłak RC, Zevaco TA, Dinjus E. Semi-synthetic zwitterionic rifamycins: a promising class of antibiotics; survey of their chemistry and biological activities. RSC Adv. 2016;6:114758–72.

    Article  CAS  Google Scholar 

  57. Baysarowich J, Koteva K, Hughes DW, Ejim L, Griffiths E, Zhang K, et al. Rifamycin antibiotic resistance by ADP-ribosylation: structure and diversity of Arr. Proc Natl Acad Sci. 2008;105:4886–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Peek J, Lilic M, Montiel D, Milshteyn A, Woodworth I, Biggins JB, et al. Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism. Nat Commun. 2018;9:4147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Wang NJ, Fu Y, Yan GH, Bao GH, Xu CF, He CH. Isolation and structure of a new ansamycin antibiotic kanglemycin A from a Nocardia. J Antibiot. 1988;41:264–7.

    Article  CAS  Google Scholar 

  60. Peek J, Xu J, Wang H, Suryavanshi S, Zimmerman M, Russo R, et al. A semisynthetic kanglemycin shows in vivo efficacy against high-burden rifampicin resistant pathogens. ACS Infect Dis. 2020;6:2431–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Calvori C, Frontali L, Leoni L, Tecce G. Effect of rifamycin on protein synthesis. Nature. 1965;207:417–8.

    Article  CAS  PubMed  Google Scholar 

  62. Hartmann G, Honikel KO, Knüsel F, Nüesch J. The specific inhibition of the DNA-directed RNA synthesis by rifamycin. Biochim Biophys Acta. 1967;145:843–4.

    Article  CAS  PubMed  Google Scholar 

  63. Umezawa H, Mizuno S, Yamazaki H, Nitta K. Inhibition of DNA-dependent RNA synthesis by rifamycins. J Antibiot. 1968;21:234–6.

    Article  CAS  Google Scholar 

  64. Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, et al. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell. 2001;104:901–12.

    Article  CAS  PubMed  Google Scholar 

  65. Goldstein BP. Resistance to rifampicin: a review. J Antibiot. 2014;67:625–30.

    Article  CAS  Google Scholar 

  66. Wehrli W. Rifampin: mechanisms of action and resistance. Rev Infect Dis. 1983;5:S407–11.

    Article  CAS  PubMed  Google Scholar 

  67. Voigt HP, Kaufmann R, Matthaei H. Solubilized DNA-dependent RNA polymerase from human placenta: A Mn(2+)-dependent enzyme. FEBS Lett. 1970;10:257–60.

    Article  CAS  PubMed  Google Scholar 

  68. Furth JJ, Nicholson A, AG E. The enzymatic synthesis of ribonucleic acid in animal tissue: III. Further purification of soluble RNA polymerase from lymphoid tissue and some general properties of the enzyme. Biochim Biophys Acta. 1970;213:124–33.

    Article  CAS  PubMed  Google Scholar 

  69. Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin, rifabutin, and rifapentine drug interactions. Curr Med Res Opin. 2013;29:1–12.

    Article  CAS  PubMed  Google Scholar 

  70. Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections. Clin Microbiol Rev. 2010;23:14–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Phillips I. Clinical uses and control of rifampicin and clindamycin. J Clin Pathol. 1971;24:410–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167:1472–7.

    Article  PubMed  Google Scholar 

  73. David HL. Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol. 1970;20:810–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. O’Neill AJ, Cove JH, Chopra I. Mutation frequencies for resistance to fusidic acid and rifampicin in Staphylococcus aureus. J Antimicrob Chemother. 2001;47:647–50.

    Article  PubMed  Google Scholar 

  75. Reynolds MG. Compensatory evolution in rifampin-resistant Escherichia coli. Genetics. 2000;156:1471–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. John AK, Baldoni D, Haschke M, Rentsch K, Schaerli P, Zimmerli W, et al. Efficacy of daptomycin in implant-associated infection due to methicillin-resistant Staphylococcus aureus: importance of combination with rifampin. Antimicrob Agents Chemother. 2009;53:2719–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jorgensen NP, Skovdal SM, Meyer RL, Dagnaes-Hansen F, Fuursted K, Petersen E. Rifampicin-containing combinations are superior to combinations of vancomycin, linezolid and daptomycin against Staphylococcus aureus biofilm infection in vivo and in vitro. Pathog Dis 2016;74:ftw019.

    Article  PubMed  CAS  Google Scholar 

  78. Yan Q, Karau MJ, Raval YS, Patel R. Evaluation of oritavancin combinations with rifampin, gentamicin, or linezolid against prosthetic joint infection-associated methicillin-resistant staphylococcus aureus biofilms by time-kill assays. Antimicrob Agents Chemother. 2018;62:e00943–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tang HJ, Chen CC, Cheng KC, Wu KY, Lin YC, Zhang CC, et al. In vitro efficacies and resistance profiles of rifampin-based combination regimens for biofilm-embedded methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013;57:5717–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wehrli W, Knusel F, Schmid K. Interaction of Rifamycin with Bacterial RNA Polymerase. Proc Natl Acad Sci USA. 1968;61:667–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Halling SM, Burtis KC, Doi RH. Reconstitution studies show that rifampicin resistance is determined by the largest polypeptide of Bacillus subtilis RNA polymerase. J Biol Chem. 1977;252:9024–31.

    Article  CAS  PubMed  Google Scholar 

  82. Andre E, Goeminne L, Cabibbe A, Beckert P, Kabamba Mukadi B, Mathys V, et al. Consensus numbering system for the rifampicin resistance-associated rpoB gene mutations in pathogenic mycobacteria. Clin Microbiol Infect. 2017;23:167–72.

    Article  CAS  PubMed  Google Scholar 

  83. Bakonyte D, Baranauskaite A, Cicenaite J, Sosnovskaja A, Stakenas P. Mutations in the rpoB gene of rifampicin-resistant Mycobacterium tuberculosis clinical isolates from Lithuania. Int J Tuberculosis Lung Dis Off J Int Union Tuberculosis Lung Dis. 2005;9:936–8.

    CAS  Google Scholar 

  84. Jamieson FB, Guthrie JL, Neemuchwala A, Lastovetska O, Melano RG, Mehaffy C. Profiling of rpoB mutations and MICs for rifampin and rifabutin in Mycobacterium tuberculosis. J Clin Microbiol. 2014;52:2157–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yue J, Shi W, Xie J, Li Y, Zeng E, Wang H. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from China. J Clin Microbiol. 2003;41:2209.LP–12.

    Article  CAS  Google Scholar 

  86. Molodtsov V, Scharf NT, Stefan MA, Garcia GA, Murakami KS. Structural basis for rifamycin resistance of bacterial RNA polymerase by the three most clinically important RpoB mutations found in Mycobacterium tuberculosis. Mol Microbiol. 2017;103:1034–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Singh A, Grover S, Sinha S, Das M, Somvanshi P, Grover A. Mechanistic principles behind molecular mechanism of rifampicin resistance in mutant RNA polymerase beta subunit of Mycobacterium tuberculosis. J Cell Biochem. 2017;118:4594–606.

    Article  CAS  PubMed  Google Scholar 

  88. Artsimovitch I, Vassylyeva MN, Svetlov D, Svetlov V, Perederina A, Igarashi N, et al. Allosteric modulation of the RNA polymerase catalytic reaction is an essential component of transcription control by rifamycins. Cell. 2005;122:351–63.

    Article  CAS  PubMed  Google Scholar 

  89. Siu GK, Zhang Y, Lau TC, Lau RW, Ho PL, Yew WW, et al. Mutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosis. J Antimicrobial Chemother. 2011;66:730–3.

    Article  CAS  Google Scholar 

  90. Khan SN, Niemann S, Gulfraz M, Qayyum M, Siddiqi S, Mirza ZS, et al. Molecular characterization of multidrug-resistant isolates of Mycobacterium tuberculosis from patients in Punjab, Pakistan. Pak J Zool. 2013;45:93–100.

    CAS  Google Scholar 

  91. Prim RI, Schörner MA, Senna SG, Nogueira CL, Figueiredo AC, Oliveira JG, et al. Molecular profiling of drug resistant isolates of Mycobacterium tuberculosis in the state of Santa Catarina, southern Brazil. Mem Inst Oswaldo Cruz. 2015;110:618–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Surette MD, Spanogiannopoulos P, Wright GD. The enzymes of the rifamycin antibiotic resistome. Acc Chem Res. 2021;54:2065–75.

    Article  CAS  PubMed  Google Scholar 

  93. Dabbs ER, Yazawa K, Mikami Y, Miyaji M, Morisaki N, Iwasaki S, et al. Ribosylation by mycobacterial strains as a new mechanism of rifampin inactivation. Antimicrob Agents Chemother. 1995;39:1007–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shin JH, Eom H, Song WJ, Rho M. Integrative metagenomic and biochemical studies on rifamycin ADP-ribosyltransferases discovered in the sediment microbiome. Sci Rep. 2018;8:12143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Rominski A, Roditscheff A, Selchow P, Böttger EC, Sander P. Intrinsic rifamycin resistance of Mycobacterium abscessus is mediated by ADP-ribosyltransferase MAB_0591. J Antimicrobial Chemother. 2017;72:376–84.

    Article  CAS  Google Scholar 

  96. Agrawal P, Miryala S, Varshney U. Use of Mycobacterium smegmatis deficient in ADP-ribosyltransferase as surrogate for Mycobacterium tuberculosis in drug testing and mutation analysis. Plos ONE. 2015;10:e0122076.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Tribuddharat C, Fennewald M. Integron-mediated rifampin resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1999;43:960–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Arlet G, Nadjar D, Herrmann JL, Donay JL, Lagrange PH, Philippon A. Plasmid-mediated rifampin resistance encoded by an arr-2-like gene cassette in Klebsiella pneumoniae producing an ACC-1 class C beta-lactamase. Antimicrob Agents Chemother. 2001;45:2971–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Girlich D, Poirel L, Leelaporn A, Karim A, Tribuddharat C, Fennewald M, et al. Molecular epidemiology of the integron-located VEB-1 extended-spectrum beta-lactamase in nosocomial enterobacterial isolates in Bangkok, Thailand. J Clin Microbiol. 2001;39:175–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Spanogiannopoulos P, Waglechner N, Koteva K, Wright GD. A rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria. Proc Natl Acad Sci. 2014;111:7102.LP–7.

    Article  CAS  Google Scholar 

  101. Stogios PJ, Cox G, Spanogiannopoulos P, Pillon MC, Waglechner N, Skarina T, et al. Rifampin phosphotransferase is an unusual antibiotic resistance kinase. Nat Commun. 2016;7:11343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Spanogiannopoulos P, Thaker M, Koteva K, Waglechner N, Wright GD. Characterization of a rifampin-inactivating glycosyltransferase from a screen of environmental actinomycetes. Antimicrobial Agents Chemother. 2012;56:5061.LP–9.

    Article  CAS  Google Scholar 

  103. Yazawa K, Mikami Y, Maeda A, Akao M, Morisaki N, Iwasaki S. Inactivation of rifampin by Nocardia brasiliensis. Antimicrob Agents Chemother. 1993;37:1313–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Andersen SJ, Quan S, Gowan B, Dabbs ER. Monooxygenase-like sequence of a Rhodococcus equi gene conferring increased resistance to rifampin by inactivating this antibiotic. Antimicrob Agents Chemother. 1997;41:218–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hoshino Y, Fujii S, Shinonaga H, Arai K, Saito F, Fukai T, et al. Monooxygenation of rifampicin catalyzed by the rox gene product of Nocardia farcinica: structure elucidation, gene identification and role in drug resistance. J Antibiot. 2010;63:23–8.

    Article  CAS  Google Scholar 

  106. Koteva K, Cox G, Kelso JK, Surette MD, Zubyk HL, Ejim L, et al. Rox, a rifamycin resistance enzyme with an unprecedented mechanism of action. Cell Chem Biol. 2018;25:403–12.e5.

    Article  CAS  PubMed  Google Scholar 

  107. Xu W, DeJesus MA, Rücker N, Engelhart CA, Wright MG, Healy C, et al. Chemical genetic interaction profiling reveals determinants of intrinsic antibiotic resistance in Mycobacterium tuberculosis. Antimicrobial Agents Chemother. 2017;61:e01334–17.

    Article  Google Scholar 

  108. Chandrasekaran S, Lalithakumari D. Plasmid-mediated rifampicin resistance in Pseudomonas fluorescens. J Med Microbiol. 1998;47:197–200.

    Article  CAS  PubMed  Google Scholar 

  109. Zhu JH, Wang BW, Pan M, Zeng YN, Rego H, Javid B. Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription. Nat Commun. 2018;9:4218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Aldridge BB, Keren I, Fortune SM. The spectrum of drug susceptibility in mycobacteria. Microbiol Spectr. 2014;2:MGM2-0031-2013.

  111. Su HW, Zhu JH, Li H, Cai RJ, Ealand C, Wang X, et al. The essential mycobacterial amidotransferase GatCAB is a modulator of specific translational fidelity. Nat Microbiol. 2016;1:16147.

    Article  CAS  PubMed  Google Scholar 

  112. Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, et al. Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol. 2019;17:441–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Andersson DI, Nicoloff H, Hjort K. Mechanisms and clinical relevance of bacterial heteroresistance. Nat Rev Microbiol. 2019;17:479–96.

    Article  CAS  PubMed  Google Scholar 

  114. El-Halfawy OM, Valvano MA. Antimicrobial heteroresistance: an emerging field in need of clarity. Clin Microbiol Rev. 2015;28:191–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Javid B, Sorrentino F, Toosky M, Zheng W, Pinkham JT, Jain N, et al. Mycobacterial mistranslation is necessary and sufficient for rifampicin phenotypic resistance. Proc Natl Acad Sci USA. 2014;111:1132–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chaudhuri S, Li L, Zimmerman M, Chen Y, Chen YX, Toosky MN, et al. Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation. eLife. 2018;7:e36782.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Cai RJ, Su HW, Li YY, Javid B. Forward genetics reveals a gatC-gatA fusion polypeptide causes mistranslation and rifampicin tolerance in Mycobacterium smegmatis. Front Microbiol. 2020;11:577756.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Brauner A, Fridman O, Gefen O, Balaban NQ. Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nat Rev Microbiol. 2016;14:320–30.

    Article  CAS  PubMed  Google Scholar 

  119. Yee R, Cui P, Shi W, Feng J, Zhang Y. Genetic screen reveals the role of purine metabolism in Staphylococcus aureus persistence to rifampicin. Antibiotics. 2015;4:627–42.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Torrey HL, Keren I, Via LE, Lee JS, Lewis K. High persister mutants in Mycobacterium tuberculosis. PloS ONE. 2016;11:e0155127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Huang X, Duan X, Li J, Niu J, Yuan S, Wang X, et al. The synergistic effect of exogenous glutamine and rifampicin against mycobacterium persisters. Front Microbiol. 2018;9:1625.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Mishra R, Kohli S, Malhotra N, Bandyopadhyay P, Mehta M, Munshi M, et al. Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis. Sci Transl Med. 2019;11:eaaw6635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Liu Y, Tan S, Huang L, Abramovitch RB, Rohde KH, Zimmerman MD, et al. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J Exp Med. 2016;213:809–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell. 2011;145:39–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hall CW, Mah TF. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol Rev. 2017;41:276–301.

    Article  CAS  PubMed  Google Scholar 

  126. Ojha AK, Baughn AD, Sambandan D, Hsu T, Trivelli X, Guerardel Y, et al. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol. 2008;69:164–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ealand C, Rimal B, Chang J, Mashigo L, Chengalroyen M, Mapela L, et al. Resuscitation-promoting factors are required for Mycobacterium smegmatis biofilm formation. Appl Environ Microbiol. 2018;84:e00687–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Sambandan D, Dao DN, Weinrick BC, Vilchèze C, Gurcha SS, Ojha A, et al. Keto-mycolic acid-dependent pellicle formation confers tolerance to drug-sensitive Mycobacterium tuberculosis. mBio. 2013;4:e00222–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Richards JP, Cai W, Zill NA, Zhang W, Ojha AK. Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance. Antimicrob Agents Chemother. 2019;63:e01213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Islam MS, Richards JP, Ojha AK. Targeting drug tolerance in mycobacteria: a perspective from mycobacterial biofilms. Expert Rev Anti Infect Ther. 2012;10:1055–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Albano M, Karau MJ, Greenwood-Quaintance KE, Osmon DR, Oravec CP, Berry DJ, et al. In vitro activity of rifampin, rifabutin, rifapentine, and rifaximin against planktonic and biofilm states of staphylococci isolated from periprosthetic joint infection. Antimicrob Agents Chemother. 2019;63:e00959–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Saginur R, Stdenis M, Ferris W, Aaron SD, Chan F, Lee C, et al. Multiple combination bactericidal testing of staphylococcal biofilms from implant-associated infections. Antimicrob Agents Chemother. 2006;50:55–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Sanchez CJ Jr., Shiels SM, Tennent DJ, Hardy SK, Murray CK, Wenke JC. Rifamycin derivatives are effective against staphylococcal biofilms in vitro and elutable from PMMA. Clin Orthop Relat Res. 2015;473:2874–84.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Singh R, Barry CE, Boshoff HIM. The three RelE homologs of Mycobacterium tuberculosis have individual, drug-specific effects on bacterial antibiotic tolerance. J Bacteriol. 2010;192:1279–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Fishbein SRS, Tomasi FG, Wolf ID, Dulberger CL, Wang A, Keshishian H, et al. The conserved translation factor LepA is required for optimal synthesis of a porin family in Mycobacterium smegmatis. J Bacteriol. 2020;203:e00604–20.

    Google Scholar 

  136. Rego EH, Audette RE, Rubin EJ. Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity. Nature. 2017;546:153–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang B-W, Zhu J-H, Javid B. Clinically relevant mutations in mycobacterial LepA cause rifampicin-specific phenotypic resistance. Sci Rep. 2020;10:8402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Riva S, Silvestri LG. Rifamycins: a general view. Annu Rev Microbiol. 1972;26:199–224.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the 250th Anniversary Fund for Innovation in Undergraduate Education, the Program for Community Engaged Scholarship, and the Council on Science and Technology at Princeton University (MPB). This content is solely the responsibility of the authors and does not necessarily represent the views of the funding agencies.

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  1. These authors contributed equally: Rebekah A. Adams, Gabrielle Leon, Natalia M. Miller, Saira P. Reyes, Chantal H. Thantrong, Alina M. Thokkadam

Authors and Affiliations

  1. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA

    Rebekah A. Adams, Gabrielle Leon, Natalia M. Miller, Saira P. Reyes, Chantal H. Thantrong, Alina M. Thokkadam, Annabel S. Lemma, Xuanqing Wan & Mark P. Brynildsen

  2. Program in Quantitative and Computational Biology, Princeton University, Princeton, NJ, USA

    Darshan M. Sivaloganathan

  3. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Mark P. Brynildsen

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RAA, GL, NMM, SPR, CHT, AMT, ASL, DMS, XW, and MPB wrote and revised the paper.

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Adams, R.A., Leon, G., Miller, N.M. et al. Rifamycin antibiotics and the mechanisms of their failure. J Antibiot 74, 786–798 (2021). https://doi.org/10.1038/s41429-021-00462-x

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