Mycobacterium tuberculosis evolutionary pathogenesis and its putative impact on drug development

Future Microbiology

Volumn 9, Issue 8, 2014, Pages 969-985

  Chevalier, Fabien Le ^a,b   Cascioferro, Alessandro ^a   Majlessi, Laleh ^a   Herrmann, Jean Louis ^c,d   Brosch, Roland ^a  

^a INSTITUT PASTEUR   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c LABORATOIRE DES SCIENCES DU CLIMAT ET DE L ENVIRONNEMENT   (France)

^d RAYMOND POINCARÉ HOSPITAL   (France)

Author keywords

attenuation; drug development; evolution; Mycobacterium tuberculosis; secretion systems; virulence factors

Indexed keywords

NEW DRUG; TUBERCULOSTATIC AGENT; VIRULENCE FACTOR;

BACTERIAL GENE; BACTERIAL GROWTH; BACTERIAL SECRETION SYSTEM; BACTERIAL VIRULENCE; DRUG DEVELOPMENT; DRUG TARGETING; ESSENTIAL GENE; GENE IDENTIFICATION; GENOMICS; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTERVENTION STUDY; MOLECULAR EVOLUTION; MOLECULAR PATHOLOGY; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; REVIEW; TUBERCULOSIS; ANIMAL; CLASSIFICATION; DRUG DESIGN; DRUG EFFECTS; GENETICS; GROWTH, DEVELOPMENT AND AGING; METABOLISM; MICROBIOLOGY; MOLECULARLY TARGETED THERAPY; MOUSE; PATHOGENICITY;

MYCOBACTERIUM TUBERCULOSIS;

ANIMALS; ANTITUBERCULAR AGENTS; DRUG DESIGN; EVOLUTION, MOLECULAR; GENES, BACTERIAL; GENES, ESSENTIAL; HUMANS; MICE; MOLECULAR TARGETED THERAPY; MYCOBACTERIUM TUBERCULOSIS; TUBERCULOSIS; VIRULENCE FACTORS;

EID: 84908042743     PISSN: 17460913     EISSN: 17460921     Source Type: Journal    
DOI: 10.2217/fmb.14.70     Document Type: Review

References (116)

1. Magee JG, Ward AC. Genus I. Mycobacterium. In: Bergey's Manual of Systematic Bacteriology, The Actinobacteria. Goodfellow M, Kämpfer P, Busse HJ et al. (Eds). Springer, NY, USA, 312-375 (2012).
2. Aitken ML, Limaye A, Pottinger P et al. Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fbrosis center. Am. J. Respir. Crit. Care Med. 185(2), 231-232 (2012).
3. Pawlik A, Garnier G, Orgeur M et al. Identifcation and characterization of the genetic changes responsible for the characteristic smooth-to-rough morphotype alterations of clinically persistent Mycobacterium abscessus. Mol. Microbiol. 90(3), 612-629 (2013).
4. Bryant JM, Grogono DM, Greaves D et al. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fbrosis: a retrospective cohort study. Lancet 381(9877), 1551-1560 (2013).
5. Shang S, Gibbs S, Henao-Tamayo M et al. Increased virulence of an epidemic strain of Mycobacterium massiliense in mice. PLoS ONE 6(9), e24726 (2011).
6. Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B. Mycobacterium abscessus: a new antibiotic nightmare. J. Antimicrob. Chemother. 67(4), 810-818 (2012).
7. Catherinot E, Roux AL, Vibet MA et al. Inhaled therapies, azithromycin and Mycobacterium abscessus in cystic fbrosis patients. Eur. Respir. J. 41(5), 1101-1106 (2013).
8. Maurer FP, Ruegger V, Ritter C, Bloemberg GV, Bottger EC. Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41). J. Antimicrob. Chemother. 67(11), 2606-2611 (2012).
9. Springer B, Stockman L, Teschner K, Roberts GD, Bottger EC. Two-laboratory collaborative study on identifcation of mycobacteria: molecular versus phenotypic methods. J. Clin. Microbiol. 34(2), 296-303 (1996).
10. Cole ST, Eiglmeier K, Parkhill J et al. Massive gene decay in the leprosy bacillus. Nature 409(6823), 1007-1011 (2001).
11. Cole S T, Brosch R, Parkhill J et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393(6685), 537-544 (1998).
12. Gordon SV, Bottai D, Simeone R, Stinear TP, Brosch R. Pathogenicity in the tubercle bacillus: molecular and evolutionary determinants. Bioessays 31(4), 378-388 (2009).
13. Stinear T P, Seemann T, Harrison PF et al. Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res. 18(5), 729-741 (2008).
14. Veyrier FJ, Dufort A, Behr MA. The rise and fall of the Mycobacterium tuberculosis genome. Trends Microbiol. 19(4), 156-161 (2011).
15. Kaur D, Guerin ME, Skovierova H, Brennan PJ, Jackson M. Chapter 2: biogenesis of the cell wall and other glycoconjugates of Mycobacterium tuberculosis. Adv. Appl. Microbiol. 69, 23-78 (2009).
16. Zuber B, Chami M, Houssin C, Dubochet J, Griffths G, Daffe M. Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J. Bacteriol. 190(16), 5672-5680 (2008).
17. Hoffmann C, Leis A, Niederweis M, Plitzko JM, Engelhardt H. Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc. Natl Acad. Sci. USA 105(10), 3963-3967 (2008).
18. Sambou T, Dinadayala P, Stadthagen G et al. Capsular glucan and intracellular glycogen of Mycobacterium tuberculosis: biosynthesis and impact on the persistence in mice. Mol. Microbiol. 70(3), 762-774 (2008).
19. Sani M, Houben EN, Geurtsen J et al. Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PLoS Pathog. 6(3), e1000794 (2010).
20. Jackson M, McNeil MR, Brennan PJ. Progress in targeting cell envelope biogenesis in Mycobacterium tuberculosis. Future Microbiol. 8(7), 855-875 (2013).
21. Ripoll F, Pasek S, Schenowitz C et al. Non mycobacterial virulence genes in the genome of the emerging pathogen Mycobacterium abscessus. PLoS ONE 4(6), e5660 (2009).
22. Gey Van Pittius NC, Sampson SL, Lee H, Kim Y, Van Helden PD, Warren RM. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol. Biol. 6, 95 (2006).
23. Supply P, Marceau M, Mangenot S et al. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis. Nat. Genet. 45, 172-179 (2013).
24. Gopinath K, Moosa A, Mizrahi V, Warner DF. Vitamin B(12) metabolism in Mycobacterium tuberculosis. Future Microbiol. 8(11), 1405-1418 (2013).
25. Genomes Online Database (GOLD). http://genomesonline.org
26. Dye C, Williams BG. The population dynamics and control of tuberculosis. Science 328(5980), 856-861 (2010).
27. Gutierrez MC, Brisse S, Brosch R et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog. 1(1), e5 (2005).
28. Comas I, Coscolla M, Luo T et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat. Genet. 45(10), 1176-1182 (2013).
29. Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defned by high density mutagenesis. Mol. Microbiol. 48(1), 77-84 (2003).
30. Sassetti CM, Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc. Natl Acad. Sci. USA 100(22), 12989-12994 (2003).
31. Griffn JE, Gawronski JD, Dejesus MA, Ioerger TR, Akerley BJ, Sassetti CM. High-resolution phenotypic profling defnes genes essential for mycobacterial growth and cholesterol catabolism. PLoS Pathog. 7(9), e1002251 (2011).
32. Fernandez P, Saint-Joanis B, Barilone N et al. The Ser/Thr protein kinase PknB is essential to sustain mycobacterial growth. J. Bacteriol. 188, 7778-7784 (2006).
33. Forti F, Crosta A, Ghisotti D. Pristinamycin-inducible gene regulation in mycobacteria. J. Biotechnol. 140 (3-4), 270-277 (2009).
34. Lougheed KE, Osborne SA, Saxty B et al. Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents. Tuberculosis (Edinb.) 91(4), 277-286 (2011).
35. Chapman TM, Bouloc N, Buxton RS et al. Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis. Bioorg. Med. Chem. Lett. 22(9), 3349-3353 (2012).
36. Raviglione MC, O'Brien RJ. Tuberculosis. In: Harrison's Principles of Internal Medicine (17th Edition). Fauci AS, Braunwald E, Kasper DL et al. (Eds). McGraw-Hill, Inc., NY, USA, 1006-1020 (2008).
37. Klopper M, Warren RM, Hayes C et al. Emergence and spread of extensively and totally drug-resistant tuberculosis, South Africa. Emerg. Infect. Dis. 19(3), 449-455 (2013).
38. Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nat. Rev. Drug Discov. 12(5), 388-404 (2013).
39. Andries K, Verhasselt P, Guillemont J et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307(5707), 223-227 (2005).
40. Diacon AH, Pym A, Grobusch M et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N. Engl. J. Med. 360(23), 2397-2405 (2009).
41. Makarov V, Manina G, Mikusova K et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324(5928), 801-804 (2009).
42. Lechartier B, Rybniker J, Zumla A, Cole ST. Tuberculosis drug discovery in the post-post-genomic era. EMBO Mol. Med. 6(2), 158-168 (2014).
43. Christophe T, Jackson M, Jeon HK et al. High content screening identifes decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog. 5(10), e1000645 (2009).
44. Pethe K, Bifani P, Jang J et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat. Med. 19 (9), 1157-1160 (2013).
45. Grzegorzewicz AE, Pham H, Gundi VA et al. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat. Chem. Biol. 8(4), 334-341 (2012).
46. Tahlan K, Wilson R, Kastrinsky DB et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56(4), 1797-1809 (2012).
47. Stover CK, Warrener P, Vandevanter DR et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405(6789), 962-966 (2000).
48. Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: novel insights from transcriptional profling. Commun. Integr. Biol. 2 (3), 215-218 (2009).
49. Wilson R, Kumar P, Parashar V et al. Antituberculosis thiophenes defne a requirement for Pks13 in mycolic acid biosynthesis. Nat. Chem. Biol. 9(8), 499-506 (2013).
50. Portevin D, De Sousa-D'auria C, Houssin C et al. A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc. Natl Acad. Sci. USA 101(1), 314-319 (2004).
51. Grosset JH, Singer TG, Bishai WR. New drugs for the treatment of tuberculosis: hope and reality. Int. J. Tuberc. Lung Dis. 16 (8), 1005-1014 (2012).
52. Lee M, Lee J, Carroll MW et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N. Engl. J. Med. 367(16), 1508-1518 (2012).
53. Williams K, Minkowski A, Amoabeng O et al. Sterilizing activities of novel combinations lacking frst-and second-line drugs in a murine model of tuberculosis. Antimicrob. Agents Chemother. 56(6), 3114-3120 (2012).
54. Hartkoorn RC, Pojer F, Read JA et al. Pyridomycin bridges the NADH-and substrate-binding pockets of the enoyl reductase InhA. Nat. Chem. Biol. 10(2), 96-98 (2013).
55. Hartkoorn RC, Sala C, Neres J et al. Towards a new tuberculosis drug: pyridomycin-nature's isoniazid. EMBO Mol. Med. 4(10), 1032-1042 (2012).
56. Willand N, Dirie B, Carette X et al. Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nat. Med. 15(5), 537-544 (2009).
57. Shi W, Zhang X, Jiang X et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 333(6049), 1630-1632 (2011).
58. Chakraborty S, Gruber T, Barry CE 3rd, Boshoff HI, Rhee KY. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science 339(6115), 88-91 (2013).
59. Ioerger TR, O'Malley T, Liao R et al. Identifcation of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS ONE 8(9), e75245 (2013).
60. Bitter W, Houben EN, Bottai D et al. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog. 5(10), e1000507 (2009).
61. Simeone R, Bottai D, Brosch R. ESX/type VII secretion systems and their role in host-pathogen interaction. Curr. Opin. Microbiol. 12(1), 4-10 (2009).
62. Siegrist MS, Unnikrishnan M, Mcconnell MJ et al. Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition. Proc. Natl Acad. Sci. USA 106(44), 18792-18797 (2009).
63. Serafni A, Boldrin F, Palu G, Manganelli R. Characterization of a Mycobacterium tuberculosis ESX-3 conditional mutant: essentiality and rescue by iron and zinc. J. Bacteriol. 191(20), 6340-6344 (2009).
64. Di Luca M, Bottai D, Batoni G et al. The ESX-5 associated eccB-eccC Locus is essential for Mycobacterium tuberculosis v iabi lit y. PLoS ONE 7(12), e52059 (2012).
65. Bottai D, Di Luca M, Majlessi L et al. Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation. Mol. Microbiol. 83(6), 1195-1209 (2012).
66. Sayes F, Sun L, Di Luca M et al. Strong Immunogenicity and cross-reactivity of Mycobacterium tuberculosis ESX-5 type VII secretion-encoded PE-PPE proteins predicts vaccine potential. Cell Host Microbe 11(4), 352-363 (2012).
67. Van Der Woude AD, Luirink J, Bitter W. Getting across the cell envelope: mycobacterial protein secretion. Curr. Top. Microbiol. Immunol. 374, 109-134 (2013).
68. Du Plessis DJ, Nouwen N, Driessen AJ. The Sec translocase. Biochim. Biophys. Acta 1808(3), 851-865 (2011).
69. Feltcher ME, Gibbons HS, Ligon LS, Braunstein M. Protein export by the mycobacterial SecA2 system is determined by the preprotein mature domain. J. Bacteriol. 195(4), 672-681 (2013).
70. Mcdonough JA, Hacker KE, Flores AR, Pavelka MS, Jr., Braunstein M. The twin-arginine translocation pathway of Mycobacterium smegmatis is functional and required for the export of mycobacterial beta-lactamases. J. Bacteriol. 187(22), 7667-7679 (2005).
71. Saint-Joanis B, Demangel C, Jackson M et al. Inactivation of Rv2525c, a substrate of the twin arginine translocation (Tat) system of Mycobacterium tuberculosis, increases beta-lactam susceptibility and virulence. J. Bacteriol. 188(18), 6669-6679 (2006).
72. Feltcher ME, Sullivan JT, Braunstein M. Protein export systems of Mycobacterium tuberculosis: novel targets for drug development? Future Microbiol. 5(10), 1581-1597 (2010).
73. Berks BC, Sargent F, Palmer T. The Tat protein export pathway. Mol. Microbiol. 35(2), 260-274 (2000).
74. Mcdonough JA, Mccann JR, Tekippe EM, Silverman JS, Rigel N W, Braunstein M. Identifcation of functional Tat signal sequences in Mycobacterium tuberculosis proteins. J. Bacteriol. 190(19), 6428-6438 (2008).
75. Raynaud C, Guilhot C, Rauzier J et al. Phospholipases C are involved in the virulence of Mycobacterium tuberculosis. Mol. Microbiol. 45 (1), 203-217 (2002).
76. Pelicic V, Jackson M, Reyrat JM, Jacobs WR Jr, Gicquel B, Guilhot C. Effcient allelic exchange and transposon mutagenesis in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 94(20), 10955-10960 (1997).
77. Bardarov S, Kriakov J, Carriere C et al. Conditionally replicating mycobacteriophages: a system for transposon delivery to Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 94, 10961-10966 (1997).
78. Camacho LR, Ensergueix D, Perez E, Gicquel B, Guilhot C. Identifcation of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol. Microbiol. 34, 257-267 (1999).
79. Cox JS, Chen B, McNeil M, Jacobs WR Jr. Complex lipid determines tissue-specifc replication of Mycobacterium tuberculosis in mice. Nature 402(6757), 79-83 (1999).
80. Braunstein M, Espinosa BJ, Chan J, Belisle JT, Jacobs WR Jr. SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis. Mol. Microbiol. 48(2), 453-464 (2003).
81. Pym AS, Saint-Joanis B, Cole ST. Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect. Immun. 70(9), 4955-4960 (2002).
82. Gagneux S, Burgos MV, Deriemer K et al. Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis. PLoS Pathog. 2(6), e 61 (2006).
83. Thillai M, Pollock K, Pareek M, Lalvani A. Interferon-gamma release assays for tuberculosis: current and future applications. Expert Rev. Respir. Med. 8(1), 67-78 (2014).
84. Van Der Wel N, Hava D, Houben D et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129, 1287-1298 (2007).
85. Simeone R, Bobard A, Lippmann J et al. Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog. 8(2), e1002507 (2012).
86. Hsu T, Hingley-Wilson SM, Chen B et al. The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc. Natl Acad. Sci. USA 100(21), 12420-12425 (2003).
87. De Jonge MI, Pehau-Arnaudet G, Fretz MM et al. ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J. Bacteriol. 189, 6028-6034 (2007).
88. De Leon J, Jiang G, Ma Y, Rubin E, Fortune S, Sun J. Mycobacterium tuberculosis E S A T-6 exhibits a unique membrane-interacting activity that is not found in its ortholog from non-pathogenic Mycobacterium smegmatis. J. Biol. Chem. 287(53), 44184-44191 (2012).
89. Houben D, Demangel C, Van Ingen J et al. ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. Cell. Microbiol. 14(8), 1287-1298 (2012).
90. Aguilo J, Alonso H, Uranga S et al. ESX-1-induced apoptosis is involved in cell-to-cell spread of Mycobacterium tuberculosis. Cell. Microbiol. 15 (12), 1994-2005 (2013).
91. Guinn KI, Hickey MJ, Mathur SK et al. Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Mol. Microbiol. 51(2), 359-370 (2004).
92. Romagnoli A, Etna MP, Giacomini E et al. ESX-1 dependent impairment of autophagic fux by Mycobacterium tuberculosis in human dendritic cells. Autophagy 8(9), 1357-1370 (2012).
93. Watson RO, Manzanillo PS, Cox JS. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150 (4), 803-815 (2012).
94. Mishra BB, Moura-Alves P, Sonawane A et al. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC infammasome. Cell. Microbiol. 12(8), 1046-1063 (2010).
95. Wong K W, Jacobs WR Jr. Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis. Cell. Microbiol. 13(9), 1371-1384 (2011).
96. Dorhoi A, Nouailles G, Jorg S et al. Activation of the NLRP3 infammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis. Eur. J. Immunol. 42(2), 374-384 (2012).
97. Stanley SA, Johndrow JE, Manzanillo P, Cox JS. The type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J. Immunol. 178 (5), 3143-3152 (2007).
98. Ryan AA, Nambiar JK, Wozniak TM et al. Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection. J. Immunol. 182(11), 7172-7177 (2009).
99. Chen JM, Pojer F, Blasco B, Cole ST. Towards anti-virulence drugs targeting ESX-1 mediated pathogenesis of Mycobacterium tuberculosis. Drug Discov. Today Dis. Mechan. 7(1), e25-e31 (2010).
100. Bottai D, Serafni A, Cascioferro A, Brosch R, Manganelli R. Targeting type VII/ESX secretion systems for development of novel antimycobacterial drugs. Curr. Pharm. Des. 20(27), 4346-4356 (2013).
101. Fortune SM, Jaeger A, Sarracino DA et al. Mutually dependent secretion of proteins required for mycobacterial virulence. Proc. Natl Acad. Sci. USA 102(30), 10676-10681 (2005).
102. Macgurn JA, Raghavan S, Stanley SA, Cox JS. A non-RD1 gene cluster is required for Snm secretion in Mycobacterium tuberculosis. Mol. Microbiol. 57(6), 1653-1663 (2005).
103. Raghavan S, Manzanillo P, Chan K, Dovey C, Cox J. Secreted transcription factor controls Mycobacterium tuberculosis virulence. Nature 454(7205), 717-721 (2008).
104. Blasco B, Chen JM, Hartkoorn R et al. Virulence regulator EspR of Mycobacterium tuberculosis is a nucleoid-associated protein. PLoS Pathog. 8(3), e1002621 (2012).
105. Frigui W, Bottai D, Majlessi L et al. Control of M. tuberculosis ESAT-6 secretion and specifc T cell recognition by PhoP. PLoS Pathog. 4(2), e33 (2008).
106. Pang X, Samten B, Cao G et al. MprAB regulates the espA operon in Mycobacterium tuberculosis and modulates ESX-1 function and host cytokine response. J. Bacteriol. 195(1), 66-75 (2013).
107. Perez E, Samper S, Bordas Y, Guilhot C, Gicquel B, Martin C. An essential role for phoP in Mycobacterium tuberculosis virulence. Mol. Microbiol. 41(1), 179-187 (2001).
108. Walters SB, Dubnau E, Kolesnikova I, Laval F, Daffe M, Smith I. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol. Microbiol. 60(2), 312-330 (2006).
109. Hunt DM, Sweeney NP, Mori L et al. Long-range transcriptional control of an operon necessary for virulence-critical ESX-1 secretion in Mycobacterium tuberculosis. J. Bacteriol. 194(9), 2307-2320 (2012).
110. Houben EN, Bestebroer J, Ummels R et al. Composition of the type VII secretion system membrane complex. Mol. Microbiol. 86(2), 472-484 (2012).
111. Bottai D, Brosch R. Mycobacterial PE, PPE and ESX clusters: novel insights into the secretion of these most unusual protein families. Mol. Microbiol. 73(3), 325-328 (2009).
112. Demangel C, Brodin P, Cockle PJ et al. Cell envelope protein PPE68 contributes to Mycobacterium tuberculosis R D1 immunogenicity independently of a 10-kilodalton culture fltrate protein and ESAT-6. Infect. Immun. 72 (4), 2170-2176 (2004).
113. Propst KL, Troyer RM, Kellihan LM, Schweizer HP, Dow SW. Immunotherapy markedly increases the effectiveness of antimicrobial therapy for treatment of Burkholderia pseudomallei infection. Antimicrob. Agents Chemother. 54(5), 1785-1792 (2010).
114. Brodin P, Poquet Y, Levillain F et al. High content phenotypic cell-based visual screen identifes Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling. PLoS Pathog. 6(9), e1001100 (2010).
115. Roetzer A, Diel R, Kohl TA et al. Whole genome sequencing versus traditional genotyping for investigation of a Mycobacterium tuberculosis outbreak: a longitudinal molecular epidemiological study. PLoS Med. 10(2), e1001387 (2013).
116. Bryant JM, Harris SR, Parkhill J et al. Whole-genome sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a retrospective observational study. Lancet Respir. Med. 1(10), 786-792 (2013).