PYRAZINAMIDE/PYRAZINOIC ACID RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS: RECENT FINDINGS AND IMPLICATIONS FOR IMPROVING THE TREATMENT OF TUBERCULOSIS

Cover Page


Cite item

Full Text

Abstract

Abstract. Pyrazinamide (PZA) is unique in that it is a component of the first line therapy for drug sensitive tuberculosis and in most current and experimental treatments also for multi drug resistant tuberculosis. Furthermore, PZA has been shown to help to ensure lasting cure and prevent relapse in shorter multi drug regimens. PZA is a prodrug. Mycobacterial tuberculosis (MTB) PncA enzyme activates the anti-mycobacterial prodrug PZA by transforming it into pyrazinoic acid (POA). The majority of clinical PZA resistant isolates contain mutations within the pncA gene and therefore remain sensitive to POA as they no longer activate PZA. Resistance to the active compound POA requires an alternative resistance mechanism and in vitro selected spontaneous MTB POA resistant mutants typically acquire a range of mutations in panD or mutations in one of a series of genes most of which are associated with the regulation of the bacterial stringent response. Clinically isolated PZA resistant MTB strains resistant to PZA and POA with mutations in any of these genes are unusual. Thus, it is likely the stringent response is critical for MTB in vivo and a damaged stringent response results in at least a reduction in fitness. Various lead compounds that disrupt the MTB stringent response have been identified that might form the basis for drugs with activity against latent mycobacteria with the potential to shorten tuberculosis treatment. Here we discuss the role of latency in the lifecycle of MTB and possible links to the activity PZA with a focus on potential new targets and drugs.

About the authors

R. M. Anthony

National Institute for Public Health and the Environment, Bilthoven

Author for correspondence.
Email: richard.anthony@rivm.nl

Richard M. Anthony, Senior Scientist, National Institute for Public Health
and the Environment (RIVM)

P.O. Box 1, 3720 BA Bilthoven, The Netherlands,
National Institute for Public Health and the Environment (RIVM).
Phone: +31302742363. Fax: +31302744418

Netherlands

A. L. den Hertog

Institute for Life Sciences and Chemistry, HU University of Applied Sciences, Utrecht

Email: fake@neicon.ru
PhD Lecturer, Institute for Life Sciences and Chemistry, HU University of Applied Sciences Netherlands

References

  1. Adams J., Kauffman M. Development of the proteasome inhibitor Velcade™ (Bortezomib). Cancer Invest., 2004, vol. 22, no. 2, pp. 304–311. doi: 10.1081/CNV-120030218
  2. Ahmad Z., Tyagi S., Minkowski A., Peloquin C.A., Grosset J.H., Nuermberger E.L. Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis. Am. J. Respir. Crit. Care Med., 2013, vol. 188, no. 1, pp. 97–102. doi: 10.1164/rccm.201212-2328OC
  3. Alumasa J.N., Manzanillo P.S., Peterson N.D., Lundrigan T., Baughn A.D., Cox J.S., Keiler K.C. Ribosome rescue inhibitors kill actively growing and nonreplicating persister Mycobacterium tuberculosis cells. ACS Inf. Dis., 2017, vol. 3, no. 9, pp. 634–644. doi: 10.1021/acsinfecdis.7b00028
  4. Anthony R.M., Cynamon M., Hoffner S., Werngren J., den Hertog A.L., van Soolingen D. Protecting pyrazinamide, a priority for improving outcomes in multidrug-resistant tuberculosis treatment. Antimicrob. Agents. Chemother., 2017, vol. 61, no. 6: e00258- 17. doi: 10.1128/AAC.00258-17
  5. Anthony R.M., den Hertog A.L., van Soolingen D. ‘Happy the man, who, studying nature’s laws, Thro’known effects can trace the secret cause.’ Do we have enough pieces to solve the pyrazinamide puzzle? J. Antimicrob. Chemother., 2018, vol. 73, no. 7, pp. 1750–1754. doi: 10.1093/jac/dky060
  6. Arenz S., Abdelshahid M., Sohmen D., Payoe R., Starosta A.L., Berninghausen O., Vasili Hauryliuk V., Beckmann R., Wilson D.N. The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis. Nucleic Acids Res., 2016, vol. 44, no. 13, pp. 6471–6481. doi: 10.1093/nar/gkw470
  7. Bag S., Das B., Dasgupta S., Bhadra R.K. Mutational analysis of the (p) ppGpp synthetase activity of the Rel enzyme of Mycobacterium tuberculosis. Arch. Microbiol., 2014, vol. 196, no. 8, pp. 575–588. doi: 10.1007/s00203-014-0996-9
  8. Black P.A., De Vos M., Louw G.E., Van der Merwe R.G., Dippenaar A., Streicher E.M., Abdallah A.M., Sampson S.L., Victor T.C., Dolby T., Simpson, J.A., van Helden, P.D., Warren, R.M., Pain A. Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates. BMC genomics, 2015, vol. 16, no. 1: 857. doi: 10.1186/s12864-015-2067-2
  9. Blanc L., Sarathy J.P., Cabrera N.A., O’Brien P., Dias-Freedman I., Mina M., Sacchettini J., Savic R.M., Gengenbacher M., Podell B.K., Prideaux B., Ioerger T., Dick T., Dartois V. Impact of immunopathology on the antituberculous activity of pyrazinamide. J. Exp. Med., 2018, vol. 215, no. 8: 1975. doi: 10.1084/jem.20180518
  10. Brunel R., Descours G., Durieux I., Doublet P., Jarraud S., Charpentier X. KKL-35 exhibits potent antibiotic activity against Legionella species independently of trans-translation inhibition. Antimicrob. Agents. Chemother., 2017, AAC-01459. doi: 10.1128/ AAC.01459-17
  11. Caño-Muñiz S., Anthony R., Niemann S., Alffenaar J.W.C. New approaches and therapeutic options for Mycobacterium tuberculosis in a dormant state. Clin. Microbiol. Rev., 2018, vol. 31, no. 1: e00060-17. doi: 10.1128/CMR.00060-17
  12. Carey A.F., Rock J.M., Krieger I.V., Chase M.R., Fernandez-Suarez M., Gagneux S., Sacchettini, J.C., Ioerger, T.R., Fortune S.M. TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities. PLoS Pathog., 2018, vol. 14, no. 3, e1006939. doi: 10.1371/journal.ppat.1006939
  13. Ciulli A., Scott D.E., Ando M., Reyes F., Saldanha S.A., Tuck K.L., Chirgadze, D.Y., Blundell, T.L., Abell C. Inhibition of Mycobacterium tuberculosis pantothenate synthetase by analogues of the reaction intermediate. ChemBioChem, 2008, vol. 9, no. 16, pp. 2606–2611. doi: 10.1002/cbic.200800437
  14. Cobelens F., Kik S., Esmail H., Cirillo D.M., Lienhardt C., Matteelli A. From latent to patent: rethinking prediction of tuberculosis. The Lancet Respiratory Medicine, 2017, vol. 5, no. 4, pp. 243–244. doi: 10.1016/S2213-2600(16)30419-2
  15. Connolly L.E., Cox J.S. CarD tricks and magic spots: mechanisms of stringent control in mycobacteria. Cell Host Microbe, 2009, vol. 6, no. 1, pp. 1–2. doi: 10.1016/j.chom.2009.07.001
  16. Datta S., Sherman J.M., Tovar M.A., Bravard M.A., Valencia T., Montoya R., Quino W., D’Arcy N., Ramos E.S., Gilman R.H., Evans C.A. Sputum microscopy with fluorescein diacetate predicts tuberculosis infectiousness. J. Infect. Dis., 2017, vol. 216, no. 5, pp. 514–524. doi: 10.1093/infdis/jix229
  17. Dillon N.A., Peterson N.D., Feaga H.A., Keiler K.C., Baughn A.D. Anti-tubercular activity of pyrazinamide is independent of trans-translation and RpsA. Scientific Reports, 2017, vol. 7, no. 1: 6135. doi: 10.1038/s41598-017-06415-5
  18. Dillon N.A., Peterson N.D., Rosen B.C., Baughn A.D. Pantothenate and pantetheine antagonize the antitubercular activity of pyrazinamide. Antimicrob. Agents Chemother., 2014, vol. 58, pp. 7258–7263. doi: 10.1128/AAC.04028-14
  19. East African/British Medical Research Councils. Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis: second report. Lancet, 1973, vol. 1, pp. 1331–1339. doi: 10.1016/S0140-6736(74)91411-1
  20. Gao W., Kim J.Y., Anderson J.R., Akopian T., Hong S., Jin Y.Y., Kandror O., Kim J.-W., Lee I.-A., Lee S.-W., McAlpine J.B., Mulugeta S., Sunoqrot S., Wang Y., Yang S.H., Yoon T-M., Goldberg A.L., Pauli G.F., Syh J.-W., Franzblau S.G., Cho S. The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo. Antimicrob. Agents. Chemother., 2014, vol. 59, no. 2, pp. 880–889. doi: 10.1128/AAC.04054-14
  21. Garton N.J., Waddell S.J., Sherratt A.L., Lee S.M., Smith R.J., Senner C., Hinds J., Rajakumar K., Adegbola R.A., Besra G.S., Butcher P.D. Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS Med., 2008, vol. 5: e75. doi: 10.1371/journal.pmed.0050075
  22. Gavrish E., Sit C.S., Cao S., Kandror O., Spoering A., Peoples A., Ling L., Fetterman A., Hughes D., Bissell A., Torrey H., Akopian T., Mueller A., Epstein S., Goldberg A., Clardy J., Lewis K. Lassomycin, a ribosomally synthesized cyclic peptide, kills Mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2. Chem. Biol., 2014, vol. 21, no. 4, pp. 509–518. doi: 10.1016/j.chembiol.2014.01.014
  23. Gillespie S.H. Evolution of drug resistance in Mycobacterium tuberculosis: clinical and molecular perspective. Antimicrob. Agents. Chemother., 2002, vol. 46, no. 2, pp. 267–274. doi: 10.1128/AAC.46.2.267-274.2002
  24. Glynn J.R., Whiteley J., Bifani P.J., Kremer K., van Soolingen D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg. Infect. Dis., 2002, vol. 8, no. 8: 843. doi: 10.3201/eid0808.020002
  25. Gomez J.E., McKinney J.D. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis, 2004, vol. 84, no. 1, pp. 29–44. doi: 10.1016/j.tube.2003.08.003
  26. Gopal P., Tasneen R., Yee M., Lanoix J.-P., Sarathy J., Rasic G., Li L., Dartois V., Nuermberger E., Dick T. In vivo-selected pyrazinoic acid-resistant Mycobacterium tuberculosis strains harbor missense mutations in the aspartate decarboxylase PanD and the unfoldase ClpC1. ACS Infect. Dis., 2017, vol. 3, pp. 492–501. doi: 10.1021/acsinfecdis.7b00017
  27. Honeyborne I., McHugh T.D., Phillips P.P., Bannoo S., Bateson A., Carroll N., Perrin F.M., Ronacher K., Wright L., Van Helden P.D., Walzl G. Molecular bacterial load assay, a culture-free biomarker for rapid and accurate quantification of sputum Mycobacterium tuberculosis bacillary load during treatment. J. Clin. Microbiol., 2011, vol. 49, no. 11, pp. 3905–3911. doi: 10.1128/JCM.00547-11
  28. Hu Y., Coates A.R., Mitchison D.A. Sterilising action of pyrazinamide in models of dormant and rifampicin-tolerant Mycobacterium tuberculosis. Int. J. Tuberc. Lung Dis., 2006, vol. 10, no. 3, pp. 317–322.
  29. Hu Y., Mangan J.A., Dhillon J., Sole K.M., Mitchison D.A., Butcher P.D., Coates A.R. Detection of mRNA transcripts and active transcription in persistent Mycobacterium tuberculosis induced by exposure to rifampin or pyrazinamide. J. Bacteriol., 2000, vol. 182, no. 22, pp. 6358–6365. doi: 10.1128/JB.182.22.6358-6365.2000
  30. Hertog A.L. den, Menting S., Pfeltz R., Warns M., Siddiqi S.H., Anthony R.M. PZA is active against Mycobacterium tuberculosis cultures at neutral pH with reduced temperature. Antimicrob. Agents. Chemother., 2016, vol. 60, no. 8, pp. 4956–4960. doi: 10.1128/AAC.00654-16.
  31. Hertog A.L. den, Menting S., van Soolingen D., Anthony R.M. Mycobacterium tuberculosis Beijing genotype resistance to transient rifampin exposure. Emerg. Infect. Dis., 2014, 20(11), 1932. doi: 10.3201/eid2011.130560
  32. Hertog A.L. den, Sengstake S., Anthony R.M. Pyrazinamide resistance in Mycobacterium tuberculosis fails to bite? Pathog. Dis., 2015, vol. 73, no. 6, doi: 10.1093/femspd/ftv037
  33. Jajou R., Kamst M., van Hunen R., de Zwaan C.C., Mulder A., Supply P., Anthony R., van der Hoek W., van Soolingen D. The occurrence and nature of double alleles in VNTR patterns of more than 8,000 Mycobacterium tuberculosis complex isolates in The Netherlands. J. Clin. Microbiol., 2017, vol. 56, iss. 2: e00761-17. doi: 10.1128/JCM.00761-17
  34. Keijzer J. de, Mulder A., de Ru A.H., van Soolingen D., van Veelen P.A. Parallel reaction monitoring of clinical Mycobacterium tuberculosis lineages reveals pre-existent markers of rifampicin tolerance in the emerging Beijing lineage. J. Proteomics, 2017, vol. 150, pp. 9–17. doi: 10.1016/j.jprot.2016.08.022
  35. Lan N.T. N., Lien H.T. K., Tung L.B., Borgdorff M.W., Kremer K., Van Soolingen D. Mycobacterium tuberculosis Beijing genotype and risk for treatment failure and relapse, Vietnam. Emerg. Infect. Dis., 2003, vol. 9, no. 12: 1633. doi: 10.3201/eid0912.030169
  36. Lee H., Suh J.W. Anti-tuberculosis lead molecules from natural products targeting Mycobacterium tuberculosis ClpC1. J. Ind. Microbiol. Biotechnol., 2016, vol. 43, no. 2–3, pp. 205–212. doi: 10.1007/s10295-015-1709-3
  37. Lillebaek T., Dirksen A., Baess I., Strunge B., Thomsen V.Ø., Andersen Å.B. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. J. Infect. Dis., 2002, vol. 185, pp. 401–404. doi: 10.1086/338342
  38. Lupoli T.J., Vaubourgeix J., Burns-Huang K., Gold B. Targeting the proteostasis network for mycobacterial drug discovery. ACS Inf. Dis., 2018, vol. 4, no. 4, pp. 478–498. doi: 10.1021/acsinfecdis.7b00231
  39. Meehan C.J., Moris P., Kohl T.A., Pecerska J., Akter S., Merker M., Utpatel C., Beckert P., Gehre F., Lempens P., Stadler T. The relationship between transmission time and clustering methods in Mycobacterium tuberculosis epidemiology. bioRxiv, 2018, 302232. doi: 10.1101/302232
  40. Miotto P., Cabibbe A.M., Feuerriegel S., Casali N., Drobniewski F., Rodionova Y., Bakonyte D., Stakenas P., Pimkina E., Augustynowicz-Kopeć. E., Degano M. Mycobacterium tuberculosis pyrazinamide resistance determinants: a multicenter study. MBio, 2014, vol. 5, no. 5: e01819-14. doi: 10.1128/mBio.01819-14
  41. Mokrousov I., Jiao W.W., Sun G.Z., Liu J.W., Valcheva V., Li M., Li M., Narvskaya O., Shen A.D. Evolution of drug resistance in different sublineages of Mycobacterium tuberculosis Beijing genotype. Antimicrob. Agents. Chemother., 2006, vol. 50, no. 8, pp. 2820–2823. doi: 10.1128/AAC.00324-06
  42. Moreira W., Ngan G.J.Y., Low J. L, Poulsen A., Chia B.C.S., Ang M.J.Y., Yap A., Fulwood J., Lakshmanan U., Lim J., Khoo A.Y.T., Flotow H., Hill J., Raju R.M., Rubin E.J., Dick T. Target mechanism-based whole-cell screening identifies bortezomib as an inhibitor of caseinolytic protease in mycobacteria. mBio, 2015, vol. 6, no. 3: e00253-15. doi: 10.1128/mBio.00253-15
  43. Moreira W., Santhanakrishnan S., Dymock B.W., Dick T. Bortezomib warhead-switch confers dual activity against mycobacterial caseinolytic protease and proteasome and selectivity against human proteasome. Front. Microbiol., 2017, vol. 8: 746. doi: 10.3389/fmicb.2017.00746
  44. Naftalin C.M., Verma R., Gurumurthy M., Lu Q., Zimmerman M., Yeo B.C.M., Tan K.H., Lin W., Yu B., Dartois V., Paton N.I. Co-administration of allopurinol to increase anti-mycobacterial efficacy of pyrazinamide: evaluation in a whole-blood bactericidal activity model. Antimicrob. Agents. Chemother., 2017, vol. 61, no. 10: e00482-17. doi: 10.1128/AAC.00482-17
  45. Njire M., Wang N., Wang B., Tan Y., Cai X., Liu Y., Mugweru J., Guo J., Hameed H.A., Tan S., Liu J. Pyrazinoic acid inhibits a bifunctional enzyme in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2017, vol. 61, no. 7: e00070-17. doi: 10.1128/AAC.00070-17
  46. Peterson N.D., Rosen B.C., Dillon N.A. Baughn A.D. Uncoupling environmental pH and intrabacterial acidification from pyrazinamide susceptibility in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2015, vol. 59, pp. 7320–7326. doi: 10.1128/ AAC.00967-15
  47. Primm T.P., Andersen S.J., Mizrahi V., Avarbock D., Rubin H., Barry C.E. The stringent response of Mycobacterium tuberculosis is required for long-term survival. J. Bacteriol., 2000, vol. 182, no. 17, pp. 4889–4898. doi: 10.1128/JB.182.17.4889-4898.2000
  48. Raju R.M., Jedrychowski M.P., Wei J.R., Pinkham J.T., Park A.S., O’Brien K., Rehren G., Schnappinger D., Gygi, S.P., Rubin E.J. Post-translational regulation via Clp protease is critical for survival of Mycobacterium tuberculosis. PLoS Pathog., 2014, vol. 10, no. 3: e1003994. doi: 10.1371/journal.ppat.1003994
  49. Raju R.M., Unnikrishnan M., Rubin D.H., Krishnamoorthy V., Kandror O., Akopian T.N., Rubin E.J. Mycobacterium tuberculosis ClpP1 and ClpP2 function together in protein degradation and are required for viability in vitro and during infection. PLoS Pathog., 2012, vol. 8, no. 2: e1002511. doi: 10.1371/journal.ppat.1002511
  50. Reed M.B., Gagneux S., DeRiemer K., Small P.M., Barry C.E. The W-Beijing lineage of Mycobacterium tuberculosis overproduces triglycerides and has the DosR dormancy regulon constitutively upregulated. J. Bacteriol., 2007, vol. 189, no. 7, pp. 2583– 2589. doi: 10.1128/JB.01670-06
  51. Rie A. van, Warren R., Richardson M., Victor T.C., Gie R.P., Enarson D.A., Beyers N., van Helden P.D. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N. Eng. J. Med., 1999, vol. 341, no. 16, pp. 1174–1179. doi: 10.1056/NEJM199910143411602
  52. Russell D.G., Barry C.E., Flynn J.L. Tuberculosis: what we don’t know can, and does, hurt us. Science, 2010, vol. 328, no. 5980, pp. 852–856. doi: 10.1126/science.1184784
  53. Schmitt E.K., Riwanto M., Sambandamurthy V., Roggo S., Miault C., Zwingelstein C., Krastel P., Noble C., Beer D., Rao S.P., Au M. The natural product cyclomarin kills Mycobacterium tuberculosis by targeting the ClpC1 subunit of the caseinolytic protease. Angewandte Chemie, 2011, vol. 123, no. 26, pp. 6011–6013. doi: 10.1002/ange.201101740
  54. Shi W., Chen J., Zhang S., Zhang W., Zhang Y. Identification of novel mutations in LprG (rv1411c), rv0521, rv3630, rv0010c, ppsC, cyp128 associated with pyrazinoic acid/pyrazinamide resistance in Mycobacterium tuberculosis. Antimicrob. Agents. Chemother., 2018, vol. 62, no. 7: e00430-18. doi: 10.1128/AAC.00430-18
  55. Shi W., Zhang X., Jiang X., Yuan H., Lee, J.S., Barry C.E., Wang H., Zhang W., Zhang, Y.Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science, 2011, vol. 333, pp. 1630–1632. doi: 10.1126/science.1208813
  56. Sreevatsan S., Pan X., Zhang Y., Kreiswirth B.N., Musser J.M. Mutations associated with pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms. Antimicrob. Agents. Chemother., 1997, vol. 41, no. 3, pp. 636–640.
  57. Stallings C.L., Stephanou N.C., Chu L., Hochschild A., Nickels B.E., Glickman M.S. CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence. Cell, 2009, vol. 138, no. 1, pp. 146–159. doi: 10.1016/j.cell.2009.04.041
  58. Syal K., Flentie K., Bhardwaj N., Maiti K., Jayaraman N., Stallings C.L., Chatterji D. Synthetic (p) ppGpp analogue: inhibitor of stringent response in mycobacteria. Antimicrob. Agents. Chemother., 2017, vol. 61, iss. 6: e00443-17. doi: 10.1128/AAC.00443-17
  59. Van Deun A., Salim H., Kumar Das A.P., Bastian I., Portaels F. Results of a standardised regimen for multidrug-resistant tuberculosis in Bangladesh. Int. J. Tuberc. Lung Dis., 2004, vol. 8, no. 5, pp. 560–567.
  60. Vasudevan D., Rao S.P., Noble C.G. Structural basis of mycobacterial inhibition by cyclomarin A. J. Biol. Chem., 2013, vol. 288, no. 43: 30883-91. doi: 10.1074/jbc.M113.493767
  61. Via L.E., Savic R., Weiner D.M., Zimmerman M.D., Prideaux B., Irwin S.M., Lyon E., O’Brien P., Gopal P., Eum S., Lee M. Host-mediated bioactivation of pyrazinamide: implications for efficacy, resistance, and therapeutic alternatives. ACS Inf. Dis., 2015, vol. 1, no. 5, pp. 203–214. doi: 10.1021/id500028m
  62. Vilchèze C., Weinrick B., Wong K.W., Chen B., Jacobs, Jr W.R. NAD+ auxotrophy is bacteriocidal for the tubercle bacilli. Mol. Microbiol., 2010, vol. 76, no. 2, pp. 365–377. doi: 10.1111/j.1365-2958.2010.07099.x
  63. Werngren J., Alm E., Mansjö M. Non-pncA Gene-mutated but pyrazinamide-resistant Mycobacterium tuberculosis: why is that? J. Clin. Microbiol., 2017, vol. 55, pp. 1920-1927. doi: 10.1128/JCM.02532-16
  64. Wexselblatt E., Oppenheimer-Shaanan Y., Kaspy I., London N., Schueler-Furman O., Yavin E., Glaser G., Katzhendler J., Ben-Yehuda S. Relacin, a novel antibacterial agent targeting the stringent response. PLoS Pathog., 2012, vol. 8, no. 9: e1002925. doi: 10.1371/journal.ppat.1002925
  65. Wollenberg K.R., Desjardins C.A., Zalutskaya A., Slodovnikova V., Oler A.J., Quiñones Abeel T., Chapman S.B., Tartakovsky M., Gabrielian A., Hoffner S., Skrahin A., Birren B.W., Rosenthal A., Skrahina A., Earl A.M. Whole-genome sequencing of Mycobacterium tuberculosis provides insight into the evolution and genetic composition of drug-resistant tuberculosis in Belarus. J. Clin. Microbiol., 2017, vol. 55, pp. 457–469. doi: 10.1128/JCM.02116-16
  66. Yee M., Gopal P., Dick T. Missense mutations in the unfoldase ClpC1 of the caseinolytic protease complex are associated with pyrazinamide resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2017, vol. 61: e02342-16. doi: 10.1128/ AAC.02342-16
  67. Zhang S., Chen J., Shi W., Cui P., Zhang J., Cho S., Zhang W., Zhang Y. Mutation in clpC1 encoding an ATP-dependent ATPase involved in protein degradation is associated with pyrazinamide resistance in Mycobacterium tuberculosis. Emerg. Microbes Infect., 2017, vol. 6: e8. doi: 10.1038/emi.2017.1

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2018 Anthony R.M., den Hertog A.L.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies