MmpL3 is the flippase for mycolic acids in mycobacteria

Proceedings of the National Academy of Sciences of the United States of America

Volumn 114, Issue 30, 2017, Pages 7993-7998

  Xu, Zhujun ^a   Meshcheryakov, Vladimir A ^a   Poce, Giovanna ^b   Chng, Shu Sin ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Drug binding; Inhibition; Lipid transport; Membrane biogenesis; Mycobacterial membrane protein Large; Trehalose monomycolate

Indexed keywords

BACTERIAL ENZYME; BACTERIAL PROTEIN; FLIPPASE; MEMBRANE PROTEIN; MYCOBACTERIAL MEMBRANE PROTEIN LARGE 3; MYCOLIC ACID; UNCLASSIFIED DRUG; BM 212; CORD FACTOR; PIPERAZINE DERIVATIVE; PYRROLE DERIVATIVE; TREHALOSE MONOMYCOLATE;

ARTICLE; BIOGENESIS; INNER MEMBRANE; MOLECULAR PROBE; MYCOBACTERIUM SMEGMATIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN TRANSPORT; SPHEROPLAST; SURFACE PROPERTY; ENZYMOLOGY; LIPID METABOLISM; METABOLISM;

BACTERIAL PROTEINS; CORD FACTORS; LIPID METABOLISM; MEMBRANE PROTEINS; MYCOBACTERIUM SMEGMATIS; MYCOLIC ACIDS; PIPERAZINES; PYRROLES; SPHEROPLASTS;

EID: 85025640419     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1700062114     Document Type: Article

References (35)

1. Brennan PJ, Nikaido H (1995) The envelope of mycobacteria. Annu Rev Biochem 64: 29–63.
2. Takayama K, Wang C, Besra GS (2005) Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18:81–101.
3. Banerjee A, et al. (1994) inhA, a gene encoding a target for isoniazid and ethion-amide in Mycobacterium tuberculosis. Science 263:227–230.
4. Jackson M, et al. (1999) Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope. Mol Microbiol 31:1573–1587.
5. Grzegorzewicz AE, et al. (2012) Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol 8:334–341.
6. Varela C, et al. (2012) MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol 19:498–506.
7. Domenech P, Reed MB, Barry CE, 3rd (2005) Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect Immun 73: 3492–3501.
8. Tahlan K, et al. (2012) 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 56:1797–1809.
9. La Rosa V, et al. (2012) MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob Agents Chemother 56:324–331.
10. Poce G, et al. (2013) Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS One 8:e56980.
11. Stanley SA, et al. (2012) Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. ACS Chem Biol 7:1377–1384.
12. Remuiñán MJ, et al. (2013) Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and N-benzyl-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3. PLoS One 8:e60933.
13. Rao SP, et al. (2013) Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Sci Transl Med 5:214ra168.
14. Lun S, et al. (2013) Indoleamides are active against drug-resistant Mycobacterium tuberculosis. Nat Commun 4:2907.
15. Dupont C, et al. (2016) A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus. Mol Microbiol 101:515–529.
16. Dhiman RK, et al. (2011) Lipoarabinomannan localization and abundance during growth of Mycobacterium smegmatis. J Bacteriol 193:5802–5809.
17. Udou T, Ogawa M, Mizuguchi Y (1982) Spheroplast formation of Mycobacterium smegmatis and morphological aspects of their reversion to the bacillary form. J Bacteriol 151:1035–1039.
18. Udou T, Ogawa M, Mizuguchi Y (1983) An improved method for the preparation of mycobacterial spheroplasts and the mechanism involved in the reversion to bacillary form: Electron microscopic and physiological study. Can J Microbiol 29:60–68.
19. Bansal-Mutalik R, Nikaido H (2014) Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimanno-sides. Proc Natl Acad Sci USA 111:4958–4963.
20. Payne KM, Hatfull GF (2012) Mycobacteriophage endolysins: Diverse and modular enzymes with multiple catalytic activities. PLoS One 7:e34052.
21. Gil F, et al. (2010) Mycobacteriophage Ms6 LysB specifically targets the outer membrane of Mycobacterium smegmatis. Microbiology 156:1497–1504.
22. Swarts BM, et al. (2012) Probing the mycobacterial trehalome with bioorthogonal chemistry. J Am Chem Soc 134:16123–16126.
23. Jewett JC, Sletten EM, Bertozzi CR (2010) Rapid Cu-free click chemistry with readily synthesized biarylazacyclooctynones. J Am Chem Soc 132:3688–3690.
24. Li W, et al. (2014) Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58:6413–6423.
25. Converse SE, et al. (2003) MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc Natl Acad Sci USA 100:6121–6126.
26. Jain M, Cox JS (2005) Interaction between polyketide synthase and transporter suggests coupled synthesis and export of virulence lipid in M. tuberculosis. PLoS Pathog 1:e2.
27. Pacheco SA, Hsu FF, Powers KM, Purdy GE (2013) MmpL11 protein transports mycolic acid-containing lipids to the mycobacterial cell wall and contributes to biofilm formation in Mycobacterium smegmatis. J Biol Chem 288:24213–24222.
28. Belardinelli JM, et al. (2014) Biosynthesis and translocation of unsulfated acyl-trehaloses in Mycobacterium tuberculosis. J Biol Chem 289:27952–27965.
29. Okuda S, Tokuda H (2011) Lipoprotein sorting in bacteria. Annu Rev Microbiol 65: 239–259.
30. Chim N, et al. (2015) The structure and interactions of periplasmic domains of crucial MmpL membrane proteins from Mycobacterium tuberculosis. Chem Biol 22: 1098–1107.
31. Belardinelli JM, et al. (2016) Structure-function profile of MmpL3, the essential mycolic acid transporter from Mycobacterium tuberculosis. ACS Infect Dis 2:702–713.
32. WHO (2016) Global Tuberculosis Report 2016. Global actions and investments fall far short of those needed to end the global TB epidemic (WHO, Geneva), WHO/HTM/TB/ 2016.13. Available at www.who.int/tb/publications/global_report/en/. Accessed December 31, 2016.
33. Li W, et al. (2016) Therapeutic potential of the Mycobacterium tuberculosis mycolic acid transporter, MmpL3. Antimicrob Agents Chemother 60:5198–5207.
34. Cox JA, et al. (2016) THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria. Nat Microbiol 1:15006.
35. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10:845–858.