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Evolution of : New Insights into Pathogenicity and Drug Resistance

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  • Authors: Eva C. Boritsch1, Roland Brosch2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
    Affiliations: 1: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, 75015 Paris, France; 2: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, 75015 Paris, France; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
  • Received 07 June 2016 Accepted 01 August 2016 Published 28 October 2016
  • R. Brosch, roland.brosch@pasteur.fr
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  • Abstract:

    The tuberculosis agent has undergone a long and selective evolution toward human infection and represents one of the most widely spread pathogens due to its efficient aerosol-mediated human-to-human transmission. With the availability of more and more genome sequences, the evolutionary trajectory of this obligate pathogen becomes visible, which provides us with new insights into the molecular events governing evolution of the bacterium and its ability to accumulate drug-resistance mutations. In this review, we summarize recent developments in mycobacterial research related to this matter that are important for a better understanding of the current situation and future trends and developments in the global epidemiology of tuberculosis, as well as for possible public health intervention possibilities.

  • Citation: Boritsch E, Brosch R. 2016. Evolution of : New Insights into Pathogenicity and Drug Resistance. Microbiol Spectrum 4(5):TBTB2-0020-2016. doi:10.1128/microbiolspec.TBTB2-0020-2016.

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RNA Polymerase beta Subunit
Tumor Necrosis Factor alpha


1. Koeck JL, Fabre M, Simon F, Daffé M, Garnotel E, Matan AB, Gérôme P, Bernatas JJ, Buisson Y, Pourcel C. 2011. Clinical characteristics of the smooth tubercle bacilli ‘Mycobacterium canettii’ infection suggest the existence of an environmental reservoir. Clin Microbiol Infect 17:1013–1019 http://dx.doi.org/10.1111/j.1469-0691.2010.03347.x. [CrossRef]
2. Supply P, Marceau M, Mangenot S, Roche D, Rouanet C, Khanna V, Majlessi L, Criscuolo A, Tap J, Pawlik A, Fiette L, Orgeur M, Fabre M, Parmentier C, Frigui W, Simeone R, Boritsch EC, Debrie AS, Willery E, Walker D, Quail MA, Ma L, Bouchier C, Salvignol G, Sayes F, Cascioferro A, Seemann T, Barbe V, Locht C, Gutierrez MC, Leclerc C, Bentley SD, Stinear TP, Brisse S, Médigue C, Parkhill J, Cruveiller S, Brosch R. 2013. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis. Nat Genet 45:172–179 http://dx.doi.org/10.1038/ng.2517. [CrossRef]
3. Springer B, Stockman L, Teschner K, Roberts GD, Böttger EC. 1996. Two-laboratory collaborative study on identification of mycobacteria: molecular versus phenotypic methods. J Clin Microbiol 34:296–303.
4. Veyrier F, Pletzer D, Turenne C, Behr MA. 2009. Phylogenetic detection of horizontal gene transfer during the step-wise genesis of Mycobacterium tuberculosis. BMC Evol Biol 9:196 http://dx.doi.org/10.1186/1471-2148-9-196. [CrossRef]
5. Tufariello JM, Kerantzas CA, Vilchèze C, Calder RB, Nordberg EK, Fischer JA, Hartman TE, Yang E, Driscoll T, Cole LE, Sebra R, Maqbool SB, Wattam AR, Jacobs WR Jr. 2015. The complete genome sequence of the emerging pathogen Mycobacterium haemophilum explains its unique culture requirements. MBio 6:e01313-15 http://dx.doi.org/10.1128/mBio.01313-15.
6. Le Chevalier F, Cascioferro A, Majlessi L, Herrmann JL, Brosch R. 2014. Mycobacterium tuberculosis evolutionary pathogenesis and its putative impact on drug development. Future Microbiol 9:969–985 http://dx.doi.org/10.2217/fmb.14.70.
7. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE III, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544 http://dx.doi.org/10.1038/31159. [CrossRef]
8. Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA, Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs WR Jr, Venter JC, Fraser CM. 2002. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol 184:5479–5490 http://dx.doi.org/10.1128/JB.184.19.5479-5490.2002. [CrossRef]
9. Roetzer A, Diel R, Kohl TA, Rückert C, Nübel U, Blom J, Wirth T, Jaenicke S, Schuback S, Rüsch-Gerdes S, Supply P, Kalinowski J, Niemann S. 2013. Whole genome sequencing versus traditional genotyping for investigation of a Mycobacterium tuberculosis outbreak: a longitudinal molecular epidemiological study. PLoS Med 10:e1001387 http://dx.doi.org/10.1371/journal.pmed.1001387.
10. Stinear TP, Seemann T, Harrison PF, Jenkin GA, Davies JK, Johnson PD, Abdellah Z, Arrowsmith C, Chillingworth T, Churcher C, Clarke K, Cronin A, Davis P, Goodhead I, Holroyd N, Jagels K, Lord A, Moule S, Mungall K, Norbertczak H, Quail MA, Rabbinowitsch E, Walker D, White B, Whitehead S, Small PL, Brosch R, Ramakrishnan L, Fischbach MA, Parkhill J, Cole ST. 2008. Insights from the complete genome sequenceof Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res 18:729–741 http://dx.doi.org/10.1101/gr.075069.107.
11. Wang J, McIntosh F, Radomski N, Dewar K, Simeone R, Enninga J, Brosch R, Rocha EP, Veyrier FJ, Behr MA. 2015. Insights on the emergence of Mycobacterium tuberculosis from the analysis of Mycobacterium kansasii. Genome Biol Evol 7:856–870 http://dx.doi.org/10.1093/gbe/evv035.
12. Stinear TP, Seemann T, Pidot S, Frigui W, Reysset G, Garnier T, Meurice G, Simon D, Bouchier C, Ma L, Tichit M, Porter JL, Ryan J, Johnson PD, Davies JK, Jenkin GA, Small PL, Jones LM, Tekaia F, Laval F, Daffé M, Parkhill J, Cole ST. 2007. Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer. Genome Res 17:192–200 http://dx.doi.org/10.1101/gr.5942807.
13. Singh P, Benjak A, Schuenemann VJ, Herbig A, Avanzi C, Busso P, Nieselt K, Krause J, Vera-Cabrera L, Cole ST. 2015. Insight into the evolution and origin of leprosy bacilli from the genome sequence of Mycobacterium lepromatosis. Proc Natl Acad Sci USA 112:4459–4464 http://dx.doi.org/10.1073/pnas.1421504112. [CrossRef]
14. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honoré N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG. 2001. Massive gene decay in the leprosy bacillus. Nature 409:1007–1011 http://dx.doi.org/10.1038/35059006. [CrossRef]
15. Comas I, Chakravartti J, Small PM, Galagan J, Niemann S, Kremer K, Ernst JD, Gagneux S. 2010. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat Genet 42:498–503 http://dx.doi.org/10.1038/ng.590. [CrossRef]
16. de Jong BC, Antonio M, Gagneux S. 2010. Mycobacterium africanum--review of an important cause of human tuberculosis in West Africa. PLoS Negl Trop Dis 4:e744 http://dx.doi.org/10.1371/journal.pntd.0000744. [CrossRef]
17. Gonzalo-Asensio J, Malaga W, Pawlik A, Astarie-Dequeker C, Passemar C, Moreau F, Laval F, Daffé M, Martin C, Brosch R, Guilhot C. 2014. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proc Natl Acad Sci USA 111:11491–11496 http://dx.doi.org/10.1073/pnas.1406693111. [CrossRef]
18. Smith NH, Kremer K, Inwald J, Dale J, Driscoll JR, Gordon SV, van Soolingen D, Hewinson RG, Smith JM. 2006. Ecotypes of the Mycobacterium tuberculosis complex. J Theor Biol 239:220–225 http://dx.doi.org/10.1016/j.jtbi.2005.08.036.
19. Garnier T, Eiglmeier K, Camus JC, Medina N, Mansoor H, Pryor M, Duthoy S, Grondin S, Lacroix C, Monsempe C, Simon S, Harris B, Atkin R, Doggett J, Mayes R, Keating L, Wheeler PR, Parkhill J, Barrell BG, Cole ST, Gordon SV, Hewinson RG. 2003. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci USA 100:7877–7882 http://dx.doi.org/10.1073/pnas.1130426100. [CrossRef]
20. van Ingen J, Rahim Z, Mulder A, Boeree MJ, Simeone R, Brosch R, van Soolingen D. 2012. Characterization of Mycobacterium orygis as M. tuberculosis complex subspecies. Emerg Infect Dis 18:653–655 http://dx.doi.org/10.3201/eid1804.110888.
21. Parsons SD, Drewe JA, Gey van Pittius NC, Warren RM, van Helden PD. 2013. Novel cause of tuberculosis in meerkats, South Africa. Emerg Infect Dis 19:2004–2007 http://dx.doi.org/10.3201/eid1912.130268. [CrossRef]
22. Cousins DV, Bastida R, Cataldi A, Quse V, Redrobe S, Dow S, Duignan P, Murray A, Dupont C, Ahmed N, Collins DM, Butler WR, Dawson D, Rodríguez D, Loureiro J, Romano MI, Alito A, Zumarraga M, Bernardelli A. 2003. Tuberculosis in seals caused by a novel member of the Mycobacterium tuberculosis complex: Mycobacterium pinnipedii sp. nov. Int J Syst Evol Microbiol 53:1305–1314 http://dx.doi.org/10.1099/ijs.0.02401-0. [CrossRef]
23. Domogalla J, Prodinger WM, Blum H, Krebs S, Gellert S, Müller M, Neuendorf E, Sedlmaier F, Büttner M. 2013. Region of difference 4 in alpine Mycobacterium caprae isolates indicates three variants. J Clin Microbiol 51:1381–1388 http://dx.doi.org/10.1128/JCM.02966-12. [CrossRef]
24. Coscolla M, Lewin A, Metzger S, Maetz-Rennsing K, Calvignac-Spencer S, Nitsche A, Dabrowski PW, Radonic A, Niemann S, Parkhill J, Couacy-Hymann E, Feldman J, Comas I, Boesch C, Gagneux S, Leendertz FH. 2013. Novel Mycobacterium tuberculosis complex isolate from a wild chimpanzee. Emerg Infect Dis 19:969–976 http://dx.doi.org/10.3201/eid1906.121012. [CrossRef]
25. Alexander KA, Sanderson CE, Larsen MH, Robbe-Austerman S, Williams MC, Palmer MV. 2016. Emerging tuberculosis pathogen hijacks social communication behavior in the group-living banded mongoose (Mungos mungo). MBio 7:e00281-16.
26. Stead WW. 1997. The origin and erratic global spread of tuberculosis. How the past explains the present and is the key to the future. Clin Chest Med 18:65–77 http://dx.doi.org/10.1016/S0272-5231(05)70356-7. [CrossRef]
27. Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, Garnier T, Gutierrez C, Hewinson G, Kremer K, Parsons LM, Pym AS, Samper S, van Soolingen D, Cole ST. 2002. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 99:3684–3689 http://dx.doi.org/10.1073/pnas.052548299. [CrossRef]
28. Mostowy S, Cousins D, Brinkman J, Aranaz A, Behr MA. 2002. Genomic deletions suggest a phylogeny for the Mycobacterium tuberculosis complex. J Infect Dis 186:74–80 http://dx.doi.org/10.1086/341068. [CrossRef]
29. Smith NH, Hewinson RG, Kremer K, Brosch R, Gordon SV. 2009. Myths and misconceptions: the origin and evolution of Mycobacterium tuberculosis. Nat Rev Microbiol 7:537–544 http://dx.doi.org/10.1038/nrmicro2165. [CrossRef]
30. Gutierrez MC, Brisse S, Brosch R, Fabre M, Omaïs B, Marmiesse M, Supply P, Vincent V. 2005. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog 1:e5 http://dx.doi.org/10.1371/journal.ppat.0010005.
31. Blouin Y, Cazajous G, Dehan C, Soler C, Vong R, Hassan MO, Hauck Y, Boulais C, Andriamanantena D, Martinaud C, Martin É, Pourcel C, Vergnaud G. 2014. Progenitor “Mycobacterium canettii” clone responsible for lymph node tuberculosis epidemic, Djibouti. Emerg Infect Dis 20:21–28 http://dx.doi.org/10.3201/eid2001.130652. [CrossRef]
32. Canetti G. 1970. [Infection caused by atypical mycobacteria and antituberculous immunity.] In French. Lille Med 15:280–282.
33. van Soolingen D, Hoogenboezem T, de Haas PE, Hermans PW, Koedam MA, Teppema KS, Brennan PJ, Besra GS, Portaels F, Top J, Schouls LM, van Embden JD. 1997. A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from Africa. Int J Syst Bacteriol 47:1236–1245 http://dx.doi.org/10.1099/00207713-47-4-1236.
34. Pfyffer GE, Auckenthaler R, van Embden JD, van Soolingen D. 1998. Mycobacterium canettii, the smooth variant of M. tuberculosis, isolated from a Swiss patient exposed in Africa. Emerg Infect Dis 4:631–634 http://dx.doi.org/10.3201/eid0404.980414.
35. Koeck JL, Bernatas JJ, Gerome P, Fabre M, Houmed A, Herve V, Teyssou R. 2002. [Epidemiology of resistance to antituberculosis drugs in Mycobacterium tuberculosis complex strains isolated from adenopathies in Djibouti. Prospective study carried out in 1999.] In French. Med Trop 62:70–72.
36. Fabre M, Koeck JL, Le Flèche P, Simon F, Hervé V, Vergnaud G, Pourcel C. 2004. High genetic diversity revealed by variable-number tandem repeat genotyping and analysis of hsp65 gene polymorphism in a large collection of “Mycobacterium canettii” strains indicates that the M. tuberculosis complex is a recently emerged clone of “M. canettii.” J Clin Microbiol 42:3248–3255 http://dx.doi.org/10.1128/JCM.42.7.3248-3255.2004. [CrossRef]
37. Fabre M, Hauck Y, Soler C, Koeck JL, van Ingen J, van Soolingen D, Vergnaud G, Pourcel C. 2010. Molecular characteristics of “Mycobacterium canettii” the smooth Mycobacterium tuberculosis bacilli. Infect Genet Evol 10:1165–1173 http://dx.doi.org/10.1016/j.meegid.2010.07.016. [CrossRef]
38. Young JS, Gormley E, Wellington EM. 2005. Molecular detection of Mycobacterium bovis and Mycobacterium bovis BCG (Pasteur) in soil. Appl Environ Microbiol 71:1946–1952 http://dx.doi.org/10.1128/AEM.71.4.1946-1952.2005. [CrossRef]
39. Mba Medie F, Ben Salah I, Henrissat B, Raoult D, Drancourt M. 2011. Mycobacterium tuberculosis complex mycobacteria as amoeba-resistant organisms. PLoS One 6:e20499 http://dx.doi.org/10.1371/journal.pone.0020499. [CrossRef]
40. Boritsch EC, Supply P, Honoré N, Seemann T, Stinear TP, Brosch R. 2014. A glimpse into the past and predictions for the future: the molecular evolution of the tuberculosis agent. Mol Microbiol 93:835–852 http://dx.doi.org/10.1111/mmi.12720.
41. Gopinath K, Moosa A, Mizrahi V, Warner DF. 2013. Vitamin B(12) metabolism in Mycobacterium tuberculosis. Future Microbiol 8:1405–1418 http://dx.doi.org/10.2217/fmb.13.113. [CrossRef]
42. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao Q, Young D, Gagneux S. 2013. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 45:1176–1182 http://dx.doi.org/10.1038/ng.2744. [CrossRef]
43. Young DB, Comas I, de Carvalho LP. 2015. Phylogenetic analysis of vitamin B12-related metabolism in Mycobacterium tuberculosis. Front Mol Biosci 2:6 http://dx.doi.org/10.3389/fmolb.2015.00006. [CrossRef]
44. Boritsch EC, Frigui W, Cascioferro A, Malaga W, Etienne G, Laval G, Pawlik A, Le Chevalier F, Orgeur M, Ma L, Bouchier C, Stinear TP, Supply P, Majlessi L, Daffé M, Guilhot C, Brosch R. 2016. pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence. Nat Microbiol 1:15019 http://dx.doi.org/10.1038/nmicrobiol.2015.19. [CrossRef]
45. Bottai D, Brosch R. 2009. Mycobacterial PE, PPE and ESX clusters: novel insights into the secretion of these most unusual protein families. Mol Microbiol 73:325–328 http://dx.doi.org/10.1111/j.1365-2958.2009.06784.x. [CrossRef]
46. Zumbo A, Palucci I, Cascioferro A, Sali M, Ventura M, D’Alfonso P, Iantomasi R, Di Sante G, Ria F, Sanguinetti M, Fadda G, Manganelli R, Delogu G. 2013. Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of Mycobacterium tuberculosis. Pathog Dis 69:232–239 http://dx.doi.org/10.1111/2049-632X.12096. [CrossRef]
47. Cascioferro A, Daleke MH, Ventura M, Donà V, Delogu G, Palù G, Bitter W, Manganelli R. 2011. Functional dissection of the PE domain responsible for translocation of PE_PGRS33 across the mycobacterial cell wall. PLoS One 6:e27713 http://dx.doi.org/10.1371/journal.pone.0027713. [CrossRef]
48. Talarico S, Cave MD, Foxman B, Marrs CF, Zhang L, Bates JH, Yang Z. 2007. Association of Mycobacterium tuberculosis PE PGRS33 polymorphism with clinical and epidemiological characteristics. Tuberculosis (Edinb) 87:338–346 http://dx.doi.org/10.1016/j.tube.2007.03.003. [CrossRef]
49. Danilchanka O, Sun J, Pavlenok M, Maueröder C, Speer A, Siroy A, Marrero J, Trujillo C, Mayhew DL, Doornbos KS, Muñoz LE, Herrmann M, Ehrt S, Berens C, Niederweis M. 2014. An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity. Proc Natl Acad Sci USA 111:6750–6755 http://dx.doi.org/10.1073/pnas.1400136111. [CrossRef]
50. Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, Nicol M, Niemann S, Kremer K, Gutierrez MC, Hilty M, Hopewell PC, Small PM. 2006. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103:2869–2873 http://dx.doi.org/10.1073/pnas.0511240103.
51. Filliol I, Motiwala AS, Cavatore M, Qi W, Hazbón MH, Bobadilla del Valle M, Fyfe J, García-García L, Rastogi N, Sola C, Zozio T, Guerrero MI, León CI, Crabtree J, Angiuoli S, Eisenach KD, Durmaz R, Joloba ML, Rendón A, Sifuentes-Osornio J, Ponce de León A, Cave MD, Fleischmann R, Whittam TS, Alland D. 2006. Global phylogeny of Mycobacterium tuberculosis based on single nucleotide polymorphism (SNP) analysis: insights into tuberculosis evolution, phylogenetic accuracy of other DNA fingerprinting systems, and recommendations for a minimal standard SNP set. J Bacteriol 188:759–772 http://dx.doi.org/10.1128/JB.188.2.759-772.2006. [CrossRef]
52. Baker L, Brown T, Maiden MC, Drobniewski F. 2004. Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis. Emerg Infect Dis 10:1568–1577 http://dx.doi.org/10.3201/eid1009.040046. [CrossRef]
53. Comas I, Hailu E, Kiros T, Bekele S, Mekonnen W, Gumi B, Tschopp R, Ameni G, Hewinson RG, Robertson BD, Goig GA, Stucki D, Gagneux S, Aseffa A, Young D, Berg S. 2015. Population genomics of Mycobacterium tuberculosis in Ethiopia contradicts the virgin soil hypothesis for human tuberculosis in Sub-Saharan Africa. Curr Biol 25:3260–3266 http://dx.doi.org/10.1016/j.cub.2015.10.061. [CrossRef]
54. Nebenzahl-Guimaraes H, Yimer SA, Holm-Hansen C, de Beer J, Brosch R, van Soolingen D. 2016. Genomic characterization of Mycobacterium tuberculosis lineage 7 and a proposed name: “Aethiops vetus.” Microb Genom 2: http://dx.doi.org/10.1099/mgen.0.000063. [CrossRef]
55. Blouin Y, Hauck Y, Soler C, Fabre M, Vong R, Dehan C, Cazajous G, Massoure PL, Kraemer P, Jenkins A, Garnotel E, Pourcel C, Vergnaud G. 2012. Significance of the identification in the Horn of Africa of an exceptionally deep branching Mycobacterium tuberculosis clade. PLoS One 7:e52841 http://dx.doi.org/10.1371/journal.pone.0052841. [CrossRef]
56. Firdessa R, Berg S, Hailu E, Schelling E, Gumi B, Erenso G, Gadisa E, Kiros T, Habtamu M, Hussein J, Zinsstag J, Robertson BD, Ameni G, Lohan AJ, Loftus B, Comas I, Gagneux S, Tschopp R, Yamuah L, Hewinson G, Gordon SV, Young DB, Aseffa A. 2013. Mycobacterial lineages causing pulmonary and extrapulmonary tuberculosis, Ethiopia. Emerg Infect Dis 19:460–463 http://dx.doi.org/10.3201/eid1903.120256. [CrossRef]
57. Reiling N, Homolka S, Walter K, Brandenburg J, Niwinski L, Ernst M, Herzmann C, Lange C, Diel R, Ehlers S, Niemann S. 2013. Clade-specific virulence patterns of Mycobacterium tuberculosis complex strains in human primary macrophages and aerogenically infected mice. MBio 4:e00250-13 http://dx.doi.org/10.1128/mBio.00250-13. [CrossRef]
58. Winglee K, Manson McGuire A, Maiga M, Abeel T, Shea T, Desjardins CA, Diarra B, Baya B, Sanogo M, Diallo S, Earl AM, Bishai WR. 2016. Whole genome sequencing of Mycobacterium africanum strains from Mali provides insights into the mechanisms of geographic restriction. PLoS Negl Trop Dis 10:e0004332 http://dx.doi.org/10.1371/journal.pntd.0004332. [CrossRef]
59. Coscolla M, Gagneux S. 2014. Consequences of genomic diversity in Mycobacterium tuberculosis. Semin Immunol 26:431–444 http://dx.doi.org/10.1016/j.smim.2014.09.012. [CrossRef]
60. de Jong BC, Hill PC, Aiken A, Awine T, Antonio M, Adetifa IM, Jackson-Sillah DJ, Fox A, Deriemer K, Gagneux S, Borgdorff MW, McAdam KP, Corrah T, Small PM, Adegbola RA. 2008. Progression to active tuberculosis, but not transmission, varies by Mycobacterium tuberculosis lineage in The Gambia. J Infect Dis 198:1037–1043 http://dx.doi.org/10.1086/591504. [CrossRef]
61. Niobe-Eyangoh SN, Kuaban C, Sorlin P, Cunin P, Thonnon J, Sola C, Rastogi N, Vincent V, Gutierrez MC. 2003. Genetic biodiversity of Mycobacterium tuberculosis complex strains from patients with pulmonary tuberculosis in Cameroon. J Clin Microbiol 41:2547–2553 http://dx.doi.org/10.1128/JCM.41.6.2547-2553.2003. [CrossRef]
62. Godreuil S, Torrea G, Terru D, Chevenet F, Diagbouga S, Supply P, Van de Perre P, Carriere C, Bañuls AL. 2007. First molecular epidemiology study of Mycobacterium tuberculosis in Burkina Faso. J Clin Microbiol 45:921–927 http://dx.doi.org/10.1128/JCM.01918-06. [CrossRef]
63. Koro Koro F, Kamdem Simo Y, Piam FF, Noeske J, Gutierrez C, Kuaban C, Eyangoh SI. 2013. Population dynamics of tuberculous Bacilli in Cameroon as assessed by spoligotyping. J Clin Microbiol 51:299–302 http://dx.doi.org/10.1128/JCM.01196-12. [CrossRef]
64. Asante-Poku A, Yeboah-Manu D, Otchere ID, Aboagye SY, Stucki D, Hattendorf J, Borrell S, Feldmann J, Danso E, Gagneux S. 2015. Mycobacterium africanum is associated with patient ethnicity in Ghana. PLoS Negl Trop Dis 9:e3370 http://dx.doi.org/10.1371/journal.pntd.0003370. [CrossRef]
65. Brites D, Gagneux S. 2012. Old and new selective pressures on Mycobacterium tuberculosis. Infect Genet Evol 12:678–685 http://dx.doi.org/10.1016/j.meegid.2011.08.010. [CrossRef]
66. Merker M, et al. 2015. Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage. Nat Genet 47:242–249 http://dx.doi.org/10.1038/ng.3195. [CrossRef]
67. van Soolingen D, Qian L, de Haas PE, Douglas JT, Traore H, Portaels F, Qing HZ, Enkhsaikan D, Nymadawa P, van Embden JD. 1995. Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia. J Clin Microbiol 33:3234–3238.
68. Luo T, Comas I, Luo D, Lu B, Wu J, Wei L, Yang C, Liu Q, Gan M, Sun G, Shen X, Liu F, Gagneux S, Mei J, Lan R, Wan K, Gao Q. 2015. Southern East Asian origin and coexpansion of Mycobacterium tuberculosis Beijing family with Han Chinese. Proc Natl Acad Sci USA 112:8136–8141 http://dx.doi.org/10.1073/pnas.1424063112. [CrossRef]
69. Mokrousov I. 2013. Insights into the origin, emergence, and current spread of a successful Russian clone of Mycobacterium tuberculosis. Clin Microbiol Rev 26:342–360 http://dx.doi.org/10.1128/CMR.00087-12. [CrossRef]
70. Frieden TR, Sherman LF, Maw KL, Fujiwara PI, Crawford JT, Nivin B, Sharp V, Hewlett D Jr, Brudney K, Alland D, Kreisworth BN. 1996. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 276:1229–1235 http://dx.doi.org/10.1001/jama.1996.03540150031027. [CrossRef]
71. Bifani PJ, Plikaytis BB, Kapur V, Stockbauer K, Pan X, Lutfey ML, Moghazeh SL, Eisner W, Daniel TM, Kaplan MH, Crawford JT, Musser JM, Kreiswirth BN. 1996. Origin and interstate spread of a New York City multidrug-resistant Mycobacterium tuberculosis clone family. JAMA 275:452–457 http://dx.doi.org/10.1001/jama.1996.03530300036037. [CrossRef]
72. Almeida D, Rodrigues C, Ashavaid TF, Lalvani A, Udwadia ZF, Mehta A. 2005. High incidence of the Beijing genotype among multidrug-resistant isolates of Mycobacterium tuberculosis in a tertiary care center in Mumbai, India. Clin Infect Dis 40:881–886 http://dx.doi.org/10.1086/427940. [CrossRef]
73. Casali N, Nikolayevskyy V, Balabanova Y, Harris SR, Ignatyeva O, Kontsevaya I, Corander J, Bryant J, Parkhill J, Nejentsev S, Horstmann RD, Brown T, Drobniewski F. 2014. Evolution and transmission of drug-resistant tuberculosis in a Russian population. Nat Genet 46:279–286 http://dx.doi.org/10.1038/ng.2878. [CrossRef]
74. Coscolla M, Barry PM, Oeltmann JE, Koshinsky H, Shaw T, Cilnis M, Posey J, Rose J, Weber T, Fofanov VY, Gagneux S, Kato-Maeda M, Metcalfe JZ. 2015. Genomic epidemiology of multidrug-resistant Mycobacterium tuberculosis during transcontinental spread. J Infect Dis 212:302–310 http://dx.doi.org/10.1093/infdis/jiv025. [CrossRef]
75. Pfyffer GE, Strässle A, van Gorkum T, Portaels F, Rigouts L, Mathieu C, Mirzoyev F, Traore H, van Embden JD. 2001. Multidrug-resistant tuberculosis in prison inmates, Azerbaijan. Emerg Infect Dis 7:855–861 http://dx.doi.org/10.3201/eid0705.017514. [CrossRef]
76. Johnson R, Warren RM, van der Spuy GD, Gey van Pittius NC, Theron D, Streicher EM, Bosman M, Coetzee GJ, van Helden PD, Victor TC. 2010. Drug-resistant tuberculosis epidemic in the Western Cape driven by a virulent Beijing genotype strain. Int J Tuberc Lung Dis 14:119–121.
77. López B, Aguilar D, Orozco H, Burger M, Espitia C, Ritacco V, Barrera L, Kremer K, Hernandez-Pando R, Huygen K, van Soolingen D. 2003. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 133:30–37 http://dx.doi.org/10.1046/j.1365-2249.2003.02171.x. [CrossRef]
78. Tsenova L, Harbacheuski R, Sung N, Ellison E, Fallows D, Kaplan G. 2007. BCG vaccination confers poor protection against M. tuberculosis HN878-induced central nervous system disease. Vaccine 25:5126–5132 http://dx.doi.org/10.1016/j.vaccine.2006.11.024. [CrossRef]
79. Parish T, Smith DA, Roberts G, Betts J, Stoker NG. 2003. The senX3-regX3 two-component regulatory system of Mycobacterium tuberculosis is required for virulence. Microbiology 149:1423–1435 http://dx.doi.org/10.1099/mic.0.26245-0. [CrossRef]
80. Marmiesse M, Brodin P, Buchrieser C, Gutierrez C, Simoes N, Vincent V, Glaser P, Cole ST, Brosch R. 2004. Macro-array and bioinformatic analyses reveal mycobacterial ‘core’ genes, variation in the ESAT-6 gene family and new phylogenetic markers for the Mycobacterium tuberculosis complex. Microbiology 150:483–496 http://dx.doi.org/10.1099/mic.0.26662-0. [CrossRef]
81. Huet G, Constant P, Malaga W, Lanéelle MA, Kremer K, van Soolingen D, Daffé M, Guilhot C. 2009. A lipid profile typifies the Beijing strains of Mycobacterium tuberculosis: identification of a mutation responsible for a modification of the structures of phthiocerol dimycocerosates and phenolic glycolipids. J Biol Chem 284:27101–27113 http://dx.doi.org/10.1074/jbc.M109.041939. [CrossRef]
82. Constant P, Perez E, Malaga W, Lanéelle MA, Saurel O, Daffé M, Guilhot C. 2002. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J Biol Chem 277:38148–38158 http://dx.doi.org/10.1074/jbc.M206538200. [CrossRef]
83. Reed MB, Domenech P, Manca C, Su H, Barczak AK, Kreiswirth BN, Kaplan G, Barry CE III. 2004. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431:84–87 http://dx.doi.org/10.1038/nature02837. [CrossRef]
84. Sinsimer D, Huet G, Manca C, Tsenova L, Koo MS, Kurepina N, Kana B, Mathema B, Marras SA, Kreiswirth BN, Guilhot C, Kaplan G. 2008. The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence. Infect Immun 76:3027–3036 http://dx.doi.org/10.1128/IAI.01663-07. [CrossRef]
85. Reed MB, Gagneux S, Deriemer K, Small PM, Barry CE III. 2007. The W-Beijing lineage of Mycobacterium tuberculosis overproduces triglycerides and has the DosR dormancy regulon constitutively upregulated. J Bacteriol 189:2583–2589 http://dx.doi.org/10.1128/JB.01670-06. [CrossRef]
86. Fallow A, Domenech P, Reed MB. 2010. Strains of the East Asian (W/Beijing) lineage of Mycobacterium tuberculosis are DosS/DosT-DosR two-component regulatory system natural mutants. J Bacteriol 192:2228–2238 http://dx.doi.org/10.1128/JB.01597-09. [CrossRef]
87. Domenech P, Kolly GS, Leon-Solis L, Fallow A, Reed MB. 2010. Massive gene duplication event among clinical isolates of the Mycobacterium tuberculosis W/Beijing family. J Bacteriol 192:4562–4570 http://dx.doi.org/10.1128/JB.00536-10. [CrossRef]
88. Ebrahimi-Rad M, Bifani P, Martin C, Kremer K, Samper S, Rauzier J, Kreiswirth B, Blazquez J, Jouan M, van Soolingen D, Gicquel B. 2003. Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. Emerg Infect Dis 9:838–845 http://dx.doi.org/10.3201/eid0907.020803. [CrossRef]
89. Merker M, Kohl TA, Roetzer A, Truebe L, Richter E, Rüsch-Gerdes S, Fattorini L, Oggioni MR, Cox H, Varaine F, Niemann S. 2013. Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients. PLoS One 8:e82551 http://dx.doi.org/10.1371/journal.pone.0082551. [CrossRef]
90. Zhang H, Li D, Zhao L, Fleming J, Lin N, Wang T, Liu Z, Li C, Galwey N, Deng J, Zhou Y, Zhu Y, Gao Y, Wang T, Wang S, Huang Y, Wang M, Zhong Q, Zhou L, Chen T, Zhou J, Yang R, Zhu G, Hang H, Zhang J, Li F, Wan K, Wang J, Zhang XE, Bi L. 2013. Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance. Nat Genet 45:1255–1260 http://dx.doi.org/10.1038/ng.2735. [CrossRef]
91. Ioerger TR, Feng Y, Chen X, Dobos KM, Victor TC, Streicher EM, Warren RM, Gey van Pittius NC, Van Helden PD, Sacchettini JC. 2010. The non-clonality of drug resistance in Beijing-genotype isolates of Mycobacterium tuberculosis from the Western Cape of South Africa. BMC Genomics 11:670 http://dx.doi.org/10.1186/1471-2164-11-670. [CrossRef]
92. Eldholm V, Monteserin J, Rieux A, Lopez B, Sobkowiak B, Ritacco V, Balloux F. 2015. Four decades of transmission of a multidrug-resistant Mycobacterium tuberculosis outbreak strain. Nat Commun 6:7119 http://dx.doi.org/10.1038/ncomms8119. [CrossRef]
93. Click ES, Moonan PK, Winston CA, Cowan LS, Oeltmann JE. 2012. Relationship between Mycobacterium tuberculosis phylogenetic lineage and clinical site of tuberculosis. Clin Infect Dis 54:211–219 http://dx.doi.org/10.1093/cid/cir788. [CrossRef]
94. Séraphin MN, Lauzardo M, Doggett RT, Zabala J, Morris JG Jr, Blackburn JK. 2016. Spatiotemporal clustering of Mycobacterium tuberculosis complex genotypes in Florida: genetic diversity segregated by country of birth. PLoS One 11:e0153575 http://dx.doi.org/10.1371/journal.pone.0153575. [CrossRef]
95. Anderson J, Jarlsberg LG, Grindsdale J, Osmond D, Kawamura M, Hopewell PC, Kato-Maeda M. 2013. Sublineages of lineage 4 (Euro-American) Mycobacterium tuberculosis differ in genotypic clustering. Int J Tuberc Lung Dis 17:885–891 http://dx.doi.org/10.5588/ijtld.12.0960. [CrossRef]
96. Lee RS, Radomski N, Proulx JF, Levade I, Shapiro BJ, McIntosh F, Soualhine H, Menzies D, Behr MA. 2015. Population genomics of Mycobacterium tuberculosis in the Inuit. Proc Natl Acad Sci USA 112:13609–13614 http://dx.doi.org/10.1073/pnas.1507071112. [CrossRef]
97. Barletta F, Otero L, de Jong BC, Iwamoto T, Arikawa K, Van der Stuyft P, Niemann S, Merker M, Uwizeye C, Seas C, Rigouts L. 2015. Predominant Mycobacterium tuberculosis families and high rates of recent transmission among new cases are not associated with primary multidrug resistance in Lima, Peru. J Clin Microbiol 53:1854–1863 http://dx.doi.org/10.1128/JCM.03585-14. [CrossRef]
98. Guerra-Assunção JA, Crampin AC, Houben RM, Mzembe T, Mallard K, Coll F, Khan P, Banda L, Chiwaya A, Pereira RP, McNerney R, Fine PE, Parkhill J, Clark TG, Glynn JR. 2015. Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area. eLife 4:e05166. http://dx.doi.org/10.7554/eLife.05166. [CrossRef]
99. Homolka S, Post E, Oberhauser B, George AG, Westman L, Dafae F, Rüsch-Gerdes S, Niemann S. 2008. High genetic diversity among Mycobacterium tuberculosis complex strains from Sierra Leone. BMC Microbiol 8:103 http://dx.doi.org/10.1186/1471-2180-8-103. [CrossRef]
100. Brudey K, et al. 2006. Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology. BMC Microbiol 6:23 http://dx.doi.org/10.1186/1471-2180-6-23. [CrossRef]
101. Lazzarini LC, Spindola SM, Bang H, Gibson AL, Weisenberg S, da Silva Carvalho W, Augusto CJ, Huard RC, Kritski AL, Ho JL. 2008. RDRio Mycobacterium tuberculosis infection is associated with a higher frequency of cavitary pulmonary disease. J Clin Microbiol 46:2175–2183 http://dx.doi.org/10.1128/JCM.00065-08. [CrossRef]
102. Lazzarini LC, Huard RC, Boechat NL, Gomes HM, Oelemann MC, Kurepina N, Shashkina E, Mello FC, Gibson AL, Virginio MJ, Marsico AG, Butler WR, Kreiswirth BN, Suffys PN, Lapa E Silva JR, Ho JL. 2007. Discovery of a novel Mycobacterium tuberculosis lineage that is a major cause of tuberculosis in Rio de Janeiro, Brazil. J Clin Microbiol 45:3891–3902 http://dx.doi.org/10.1128/JCM.01394-07. [CrossRef]
103. Gibson AL, Huard RC, Gey van Pittius NC, Lazzarini LC, Driscoll J, Kurepina N, Zozio T, Sola C, Spindola SM, Kritski AL, Fitzgerald D, Kremer K, Mardassi H, Chitale P, Brinkworth J, Garcia de Viedma D, Gicquel B, Pape JW, van Soolingen D, Kreiswirth BN, Warren RM, van Helden PD, Rastogi N, Suffys PN, Lapa e Silva J, Ho JL. 2008. Application of sensitive and specific molecular methods to uncover global dissemination of the major RDRio Sublineage of the Latin American-Mediterranean Mycobacterium tuberculosis spoligotype family. J Clin Microbiol 46:1259–1267 http://dx.doi.org/10.1128/JCM.02231-07. [CrossRef]
104. Weisenberg SA, Gibson AL, Huard RC, Kurepina N, Bang H, Lazzarini LC, Chiu Y, Li J, Ahuja S, Driscoll J, Kreiswirth BN, Ho JL. 2012. Distinct clinical and epidemiological features of tuberculosis in New York City caused by the RD(Rio) Mycobacterium tuberculosis sublineage. Infect Genet Evol 12:664–670 http://dx.doi.org/10.1016/j.meegid.2011.07.018.
105. Majlessi L, Prados-Rosales R, Casadevall A, Brosch R. 2015. Release of mycobacterial antigens. Immunol Rev 264:25–45 http://dx.doi.org/10.1111/imr.12251. [CrossRef]
106. Von Groll A, Martin A, Felix C, Prata PF, Honscha G, Portaels F, Vandame P, da Silva PE, Palomino JC. 2010. Fitness study of the RDRio lineage and Latin American-Mediterranean family of Mycobacterium tuberculosis in the city of Rio Grande, Brazil. FEMS Immunol Med Microbiol 58:119–127 http://dx.doi.org/10.1111/j.1574-695X.2009.00611.x. [CrossRef]
107. Kremer K, van Soolingen D, Frothingham R, Haas WH, Hermans PW, Martín C, Palittapongarnpim P, Plikaytis BB, Riley LW, Yakrus MA, Musser JM, van Embden JD. 1999. Comparison of methods based on different molecular epidemiological markers for typing of Mycobacterium tuberculosis complex strains: interlaboratory study of discriminatory power and reproducibility. J Clin Microbiol 37:2607–2618.
108. Ritacco V, Di Lonardo M, Reniero A, Ambroggi M, Barrera L, Dambrosi A, Lopez B, Isola N, de Kantor IN. 1997. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 176:637–642 http://dx.doi.org/10.1086/514084.
109. Palmero D, Ritacco V, Ambroggi M, Natiello M, Barrera L, Capone L, Dambrosi A, di Lonardo M, Isola N, Poggi S, Vescovo M, Abbate E. 2003. Multidrug-resistant tuberculosis in HIV-negative patients, Buenos Aires, Argentina. Emerg Infect Dis 9:965–969 http://dx.doi.org/10.3201/eid0908.020474. [CrossRef]
110. Kubín M, Havelková M, Hyncicová I, Svecová Z, Kaustová J, Kremer K, van Soolingen D. 1999. A multidrug-resistant tuberculosis microepidemic caused by genetically closely related Mycobacterium tuberculosis strains. J Clin Microbiol 37:2715–2716.
111. Mardassi H, Namouchi A, Haltiti R, Zarrouk M, Mhenni B, Karboul A, Khabouchi N, Gey van Pittius NC, Streicher EM, Rauzier J, Gicquel B, Dellagi K. 2005. Tuberculosis due to resistant Haarlem strain, Tunisia. Emerg Infect Dis 11:957–961 http://dx.doi.org/10.3201/eid1106.041365. [CrossRef]
112. Ramazanzadeh R, Roshani D, Shakib P, Rouhi S. 2015. Prevalence and occurrence rate of Mycobacterium tuberculosis Haarlem family multi-drug resistant in the worldwide population: A systematic review and meta-analysis. J Res Med Sci 20:78–88.
113. Olano J, López B, Reyes A, Lemos MP, Correa N, Del Portillo P, Barrera L, Robledo J, Ritacco V, Zambrano MM. 2007. Mutations in DNA repair genes are associated with the Haarlem lineage of Mycobacterium tuberculosis independently of their antibiotic resistance. Tuberculosis (Edinb) 87:502–508 http://dx.doi.org/10.1016/j.tube.2007.05.011. Edinb [CrossRef]
114. Mortimer TD, Pepperell CS. 2014. Genomic signatures of distributive conjugal transfer among mycobacteria. Genome Biol Evol 6:2489–2500 http://dx.doi.org/10.1093/gbe/evu175. [CrossRef]
115. Gray TA, Krywy JA, Harold J, Palumbo MJ, Derbyshire KM. 2013. Distributive conjugal transfer in mycobacteria generates progeny with meiotic-like genome-wide mosaicism, allowing mapping of a mating identity locus. PLoS Biol 11:e1001602 http://dx.doi.org/10.1371/journal.pbio.1001602.
116. Boritsch EC, Khanna V, Pawlik A, Honoré N, Navas VH, Ma L, Bouchier L, Seemann T, Supply P, Stinear TP, Brosch R. Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria. Proc Natl Acad Sci USA 113:9876–9881. doi:10.1073/pnas.1604921113. [CrossRef]
117. Schatz A, Waksman SA. 1944. Effect of streptomycin and other antibiotic substances upon Mycobacterium tuberculosis and related organisms. Proc Soc Exp Biol Med 57:244–248 http://dx.doi.org/10.3181/00379727-57-14769. [CrossRef]
118. Medical Research Council. 1952. Treatment of pulmonary tuberculosis with isoniazid; an interim report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. BMJ 2:735–746 http://dx.doi.org/10.1136/bmj.2.4787.735. [CrossRef]
119. Sensi P. 1983. History of the development of rifampin. Rev Infect Dis 5(Suppl 3):S402–S406 http://dx.doi.org/10.1093/clinids/5.Supplement_3.S402. [CrossRef]
120. Canetti G. 1965. Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 92:687–703.
121. Lienhardt C, Vernon A, Raviglione MC. 2010. New drugs and new regimens for the treatment of tuberculosis: review of the drug development pipeline and implications for national programmes. Curr Opin Pulm Med 16:186–193. [CrossRef]
122. Gardy JL, Johnston JC, Ho Sui SJ, Cook VJ, Shah L, Brodkin E, Rempel S, Moore R, Zhao Y, Holt R, Varhol R, Birol I, Lem M, Sharma MK, Elwood K, Jones SJ, Brinkman FS, Brunham RC, Tang P. 2011. Whole-genome sequencing and social-network analysis of a tuberculosis outbreak. N Engl J Med 364:730–739 http://dx.doi.org/10.1056/NEJMoa1003176. [CrossRef]
123. Mitruka K, Oeltmann JE, Ijaz K, Haddad MB. 2011. Tuberculosis outbreak investigations in the United States, 2002-2008. Emerg Infect Dis 17:425–431 http://dx.doi.org/10.3201/eid1703.101550. [CrossRef]
124. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, Zeller K, Andrews J, Friedland G. 2006. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368:1575–1580 http://dx.doi.org/10.1016/S0140-6736(06)69573-1. [CrossRef]
125. Stucki D, Ballif M, Bodmer T, Coscolla M, Maurer AM, Droz S, Butz C, Borrell S, Längle C, Feldmann J, Furrer H, Mordasini C, Helbling P, Rieder HL, Egger M, Gagneux S, Fenner L. 2015. Tracking a tuberculosis outbreak over 21 years: strain-specific single-nucleotide polymorphism typing combined with targeted whole-genome sequencing. J Infect Dis 211:1306–1316.
126. Centers for Disease Control and Prevention (CDC). 2006. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs--worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep 55:301–305.
127. WHO. 2015. Global Tuberculosis Report 2015. World Health Organization, Geneva, Switzerland.
128. Telenti A, Imboden P, Marchesi F, Matter L, Schopfer K, Bodmer T, Lowrie D, Colston MJ, Cole, S. 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341:647–651 http://dx.doi.org/10.1016/0140-6736(93)90417-F. [CrossRef]
129. Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ. 2006. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944–1946 http://dx.doi.org/10.1126/science.1124410. [CrossRef]
130. Meftahi N, Namouchi A, Mhenni B, Brandis G, Hughes D, Mardassi H. 2016. Evidence for the critical role of a secondary site rpoB mutation in the compensatory evolution and successful transmission of an MDR tuberculosis outbreak strain. J Antimicrob Chemother 71:324–332 http://dx.doi.org/10.1093/jac/dkv345. [CrossRef]
131. Brandis G, Pietsch F, Alemayehu R, Hughes D. 2015. Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 70:680–685 http://dx.doi.org/10.1093/jac/dku434. [CrossRef]
132. Zhang Y, Heym B, Allen B, Young D, Cole S. 1992. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591–593 http://dx.doi.org/10.1038/358591a0. [CrossRef]
133. Cade CE, Dlouhy AC, Medzihradszky KF, Salas-Castillo SP, Ghiladi RA. 2010. Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities. Protein Sci 19:458–474.
134. Ghiladi RA, Medzihradszky KF, Rusnak FM, Ortiz de Montellano PR. 2005. Correlation between isoniazid resistance and superoxide reactivity in mycobacterium tuberculosis KatG. J Am Chem Soc 127:13428–13442 http://dx.doi.org/10.1021/ja054366t. [CrossRef]
135. Shoeb HA, Bowman BU Jr, Ottolenghi AC, Merola AJ. 1985. Peroxidase-mediated oxidation of isoniazid. Antimicrob Agents Chemother 27:399–403 http://dx.doi.org/10.1128/AAC.27.3.399. [CrossRef]
136. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR Jr. 1994. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227–230 http://dx.doi.org/10.1126/science.8284673. [CrossRef]
137. Manca C, Paul S, Barry CE III, Freedman VH, Kaplan G. 1999. Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro. Infect Immun 67:74–79.
138. Middlebrook G, Cohn ML. 1953. Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli. Science 118:297–299 http://dx.doi.org/10.1126/science.118.3063.297. [CrossRef]
139. Li Z, Kelley C, Collins F, Rouse D, Morris S. 1998. Expression of katG in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs. J Infect Dis 177:1030–1035 http://dx.doi.org/10.1086/515254. [CrossRef]
140. Pym AS, Saint-Joanis B, Cole ST. 2002. Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect Immun 70:4955–4960 http://dx.doi.org/10.1128/IAI.70.9.4955-4960.2002. [CrossRef]
141. Sherman DR, Mdluli K, Hickey MJ, Arain TM, Morris SL, Barry CE III, Stover CK. 1996. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272:1641–1643 http://dx.doi.org/10.1126/science.272.5268.1641. [CrossRef]
142. Guo H, Seet Q, Denkin S, Parsons L, Zhang Y. 2006. Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol 55:1527–1531 http://dx.doi.org/10.1099/jmm.0.46718-0. [CrossRef]
143. Safi H, Lingaraju S, Amin A, Kim S, Jones M, Holmes M, McNeil M, Peterson SN, Chatterjee D, Fleischmann R, Alland D. 2013. Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes. Nat Genet 45:1190–1197 http://dx.doi.org/10.1038/ng.2743.
144. Eldholm V, Balloux F. 2016. Antimicrobial resistance in Mycobacterium tuberculosis: the odd one out. Trends Microbiol 24:637–648 http://dx.doi.org/10.1016/j.tim.2016.03.007. [CrossRef]
145. Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. 1993. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 328:521–526 http://dx.doi.org/10.1056/NEJM199302253280801. [CrossRef]
146. Rullán JV, Herrera D, Cano R, Moreno V, Godoy P, Peiró EF, Castell J, Ibañez C, Ortega A, Agudo LS, Pozo F. 1996. Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain. Emerg Infect Dis 2:125–129 http://dx.doi.org/10.3201/eid0202.960208. [CrossRef]
147. Hannan MM, Peres H, Maltez F, Hayward AC, Machado J, Morgado A, Proenca R, Nelson MR, Bico J, Young DB, Gazzard BS. 2001. Investigation and control of a large outbreak of multi-drug resistant tuberculosis at a central Lisbon hospital. J Hosp Infect 47:91–97 http://dx.doi.org/10.1053/jhin.2000.0884. [CrossRef]
148. Harries AD, Kamenya A, Namarika D, Msolomba IW, Salaniponi FM, Nyangulu DS, Nunn P. 1997. Delays in diagnosis and treatment of smear-positive tuberculosis and the incidence of tuberculosis in hospital nurses in Blantyre, Malawi. Trans R Soc Trop Med Hyg 91:15–17 http://dx.doi.org/10.1016/S0035-9203(97)90376-X. [CrossRef]
149. Cohen KA, Abeel T, Manson McGuire A, Desjardins CA, Munsamy V, Shea TP, Walker BJ, Bantubani N, Almeida DV, Alvarado L, Chapman SB, Mvelase NR, Duffy EY, Fitzgerald MG, Govender P, Gujja S, Hamilton S, Howarth C, Larimer JD, Maharaj K, Pearson MD, Priest ME, Zeng Q, Padayatchi N, Grosset J, Young SK, Wortman J, Mlisana KP, O’Donnell MR, Birren BW, Bishai WR, Pym AS, Earl AM. 2015. Evolution of extensively drug-resistant tuberculosis over four decades: whole genome sequencing and dating analysis of Mycobacterium tuberculosis isolates from KwaZulu-Natal. PLoS Med 12:e1001880 http://dx.doi.org/10.1371/journal.pmed.1001880. [CrossRef]
150. Sun G, Luo T, Yang C, Dong X, Li J, Zhu Y, Zheng H, Tian W, Wang S, Barry CE III, Mei J, Gao Q. 2012. Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients. J Infect Dis 206:1724–1733 http://dx.doi.org/10.1093/infdis/jis601. [CrossRef]
151. Casali N, Nikolayevskyy V, Balabanova Y, Ignatyeva O, Kontsevaya I, Harris SR, Bentley SD, Parkhill J, Nejentsev S, Hoffner SE, Horstmann RD, Brown T, Drobniewski F. 2012. Microevolution of extensively drug-resistant tuberculosis in Russia. Genome Res 22:735–745 http://dx.doi.org/10.1101/gr.128678.111. [CrossRef]
152. Phelan J, Coll F, McNerney R, Ascher DB, Pires DE, Furnham N, Coeck N, Hill-Cawthorne GA, Nair MB, Mallard K, Ramsay A, Campino S, Hibberd ML, Pain A, Rigouts L, Clark TG. 2016. Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. BMC Med 14:31 http://dx.doi.org/10.1186/s12916-016-0575-9. [CrossRef]
153. Comas I, Borrell S, Roetzer A, Rose G, Malla B, Kato-Maeda M, Galagan J, Niemann S, Gagneux S. 2011. Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat Genet 44:106–110 http://dx.doi.org/10.1038/ng.1038. [CrossRef]
154. Walker TM, Kohl TA, Omar SV, Hedge J, Del Ojo Elias C, Bradley P, Iqbal Z, Feuerriegel S, Niehaus KE, Wilson DJ, Clifton DA, Kapatai G, Ip CL, Bowden R, Drobniewski FA, Allix-Béguec C, Gaudin C, Parkhill J, Diel R, Supply P, Crook DW, Smith EG, Walker AS, Ismail N, Niemann S, Peto TE, Modernizing Medical Microbiology (MMM) Informatics Group. 2015. Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. Lancet Infect Dis 15:1193–1202 http://dx.doi.org/10.1016/S1473-3099(15)00062-6. [CrossRef]
155. Shenai S, Amisano D, Ronacher K, Kriel M, Banada PP, Song T, Lee M, Joh JS, Winter J, Thayer R, Via LE, Kim S, Barry CE III, Walzl G, Alland D. 2013. Exploring alternative biomaterials for diagnosis of pulmonary tuberculosis in HIV-negative patients by use of the GeneXpert MTB/RIF assay. J Clin Microbiol 51:4161–4166 http://dx.doi.org/10.1128/JCM.01743-13. [CrossRef]
156. Desjardins CA, Cohen KA, Munsamy V, Abeel T, Maharaj K, Walker BJ, Shea TP, Almeida DV, Manson AL, Salazar A, Padayatchi N, O’Donnell MR, Mlisana KP, Wortman J, Birren BW, Grosset J, Earl AM, Pym AS. 2016. Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance. Nat Genet 48:544–551 http://dx.doi.org/10.1038/ng.3548. [CrossRef]
157. Takiff HE, Feo O. 2015. Clinical value of whole-genome sequencing of Mycobacterium tuberculosis. Lancet Infect Dis 15:1077–1090 http://dx.doi.org/10.1016/S1473-3099(15)00071-7. [CrossRef]
158. Warner DF, Mizrahi V. 2013. Complex genetics of drug resistance in Mycobacterium tuberculosis. Nat Genet 45:1107–1108 http://dx.doi.org/10.1038/ng.2769. [CrossRef]
159. Farhat MR, Shapiro BJ, Kieser KJ, Sultana R, Jacobson KR, Victor TC, Warren RM, Streicher EM, Calver A, Sloutsky A, Kaur D, Posey JE, Plikaytis B, Oggioni MR, Gardy JL, Johnston JC, Rodrigues M, Tang PK, Kato-Maeda M, Borowsky ML, Muddukrishna B, Kreiswirth BN, Kurepina N, Galagan J, Gagneux S, Birren B, Rubin EJ, Lander ES, Sabeti PC, Murray M. 2013. Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis. Nat Genet 45:1183–1189 http://dx.doi.org/10.1038/ng.2747. [CrossRef]
160. Pérez-Lago L, Comas I, Navarro Y, González-Candelas F, Herranz M, Bouza E, García-de-Viedma D. 2014. Whole genome sequencing analysis of intrapatient microevolution in Mycobacterium tuberculosis: potential impact on the inference of tuberculosis transmission. J Infect Dis 209:98–108 http://dx.doi.org/10.1093/infdis/jit439. [CrossRef]
161. Pérez-Lago L, Palacios JJ, Herranz M, Ruiz Serrano MJ, Bouza E, García-de-Viedma D. 2015. Revealing hidden clonal complexity in Mycobacterium tuberculosis infection by qualitative and quantitative improvement of sampling. Clin Microbiol Infect 21:147.e1–147.e7 http://dx.doi.org/10.1016/j.cmi.2014.09.015. [CrossRef]
162. Eldholm V, Norheim G, von der Lippe B, Kinander W, Dahle UR, Caugant DA, Mannsåker T, Mengshoel AT, Dyrhol-Riise AM, Balloux F. 2014. Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient. Genome Biol 15:490 http://dx.doi.org/10.1186/s13059-014-0490-3. [CrossRef]
163. Black PA, de Vos M, Louw GE, van der Merwe RG, Dippenaar A, Streicher EM, Abdallah AM, Sampson SL, Victor TC, Dolby T, Simpson JA, van Helden PD, Warren RM, Pain A. 2015. Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates. BMC Genomics 16:857 http://dx.doi.org/10.1186/s12864-015-2067-2. [CrossRef]
164. Liu Q, Via LE, Luo T, Liang L, Liu X, Wu S, Shen Q, Wei W, Ruan X, Yuan X, Zhang G, Barry CE III, Gao Q. 2015. Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment. Sci Rep 5:17507 http://dx.doi.org/10.1038/srep17507. [CrossRef]
165. Niemann S, Köser CU, Gagneux S, Plinke C, Homolka S, Bignell H, Carter RJ, Cheetham RK, Cox A, Gormley NA, Kokko-Gonzales P, Murray LJ, Rigatti R, Smith VP, Arends FP, Cox HS, Smith G, Archer JA. 2009. Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints. PLoS One 4:e7407 http://dx.doi.org/10.1371/journal.pone.0007407. [CrossRef]
166. Ioerger TR, Koo S, No EG, Chen X, Larsen MH, Jacobs WR Jr, Pillay M, Sturm AW, Sacchettini JC. 2009. Genome analysis of multi- and extensively-drug-resistant tuberculosis from KwaZulu-Natal, South Africa. PLoS One 4:e7778 http://dx.doi.org/10.1371/journal.pone.0007778. [CrossRef]

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The tuberculosis agent has undergone a long and selective evolution toward human infection and represents one of the most widely spread pathogens due to its efficient aerosol-mediated human-to-human transmission. With the availability of more and more genome sequences, the evolutionary trajectory of this obligate pathogen becomes visible, which provides us with new insights into the molecular events governing evolution of the bacterium and its ability to accumulate drug-resistance mutations. In this review, we summarize recent developments in mycobacterial research related to this matter that are important for a better understanding of the current situation and future trends and developments in the global epidemiology of tuberculosis, as well as for possible public health intervention possibilities.

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Image of FIGURE 1

Scheme showing supposed molecular key events in mycobacterial evolution from a recombinogenic strain pool toward professional pathogens of mammalian hosts. Network phylogeny inferred among eight strains and 46 selected genome sequences from MTBC members by NeighborNet analysis. Pairwise alignments of whole genome SNP data are the basis of the calculation. Recombination of and deletion of in a potential progenitor of the MTBC strains illustrated in the inset. Figure reproduced from reference 44 .

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Image of FIGURE 2

Neighbor-joining phylogeny scheme based on variable nucleotide positions with main focus on tubercle bacilli that have a human host preference, using as root of the tree (after reference 56 ). The filtered SNPs refer to the mutations identified between the various strains relative to H37Rv ( 15 ). Figure reproduced from reference 40 .

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Image of FIGURE 3a

Overview of a large number of potential drug resistance as well as compensatory mutations against first- and second-line drugs. Mutations shown in bold represent most commonly found mutations among resistant strains. Semibold secondary mutations in , and were found to be shared by related strains, thus suggesting mutations favoring transmission. Any mutations leading to at least rifampin and isoniazid resistance confer an MDR phenotype, whereas MDR strains with additional mutations against at least one of the three injectable drugs, kanamycin, amikacin, and capreomycin, and to any fluoroquinolone used against are referred to as XDR strains. Table based on mutations found in the following publications ( 50 , 58 , 73 , 89 , 91 , 92 , 130 , 133 , 142 , 143 , 149 , 151 154 , 156 , 163 , 166 ).

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Image of FIGURE 3b

Overview of a large number of potential drug resistance as well as compensatory mutations against first- and second-line drugs. Mutations shown in bold represent most commonly found mutations among resistant strains. Semibold secondary mutations in , and were found to be shared by related strains, thus suggesting mutations favoring transmission. Any mutations leading to at least rifampin and isoniazid resistance confer an MDR phenotype, whereas MDR strains with additional mutations against at least one of the three injectable drugs, kanamycin, amikacin, and capreomycin, and to any fluoroquinolone used against are referred to as XDR strains. Table based on mutations found in the following publications ( 50 , 58 , 73 , 89 , 91 , 92 , 130 , 133 , 142 , 143 , 149 , 151 154 , 156 , 163 , 166 ).

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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Image of FIGURE 4

Suggested model for a selection bottleneck followed by random mutations on the population structure of clinical isolates. Genetic diversity of subpopulations is present in a rifampin monoresistant clinical isolate (each individual bacterium contains a rifampin resistance-conferring mutation). Upon isoniazid treatment clones carrying low-cost resistance mutations to the drug become dominant and prevail over other variants, resulting in the loss of numerous other genetic mutations. Subsequent repeated genetic diversification results in genomic heterogeneity of the MDR strain population. x represents an isoniazid resistance-causing mutation. Figure adapted from reference 163 .

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.TBTB2-0020-2016
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