Abstract
Tuberculosis caused by Mycobacterium tuberculosis remains a serious threat to public health. The M. tuberculosis cell envelope is closely related to its virulence and drug resistance. Mycobacterial membrane large proteins (MmpL) are lipid-transporting proteins of the efflux pump resistance nodulation cell division (RND) superfamily with lipid substrate specificity and non-transport lipid function. Mycobacterial membrane small proteins (MmpS) are small regulatory proteins, and they are also responsible for some virulence-related effects as accessory proteins of MmpL. The MmpL transporters are the candidate targets for the development of anti-tuberculosis drugs. This article summarizes the structure, function, phylogenetics of M. tuberculosis MmpL/S proteins and their roles in host immune response, inhibitors and regulatory system.
Funding source: National Natural Science Foundation
Award Identifier / Grant number: 81871182
Award Identifier / Grant number: 81371851
Funding statement: This article was supported by National Natural Science Foundation, Funder Id: http://dx.doi.org/10.13039/501100001809 (Grant numbers 81871182 and 81371851), National key R & D plan (2016YFC0502304), and the Fundamental Research Funds for the Central Universities (Grant numbers XDJK2017D101, XDJK2017D100 and XDJK2017D099).
Conflict of interest statement: The authors declare no conflicts of interest.
References
Adams, K.N., Szumowski, J.D., and Ramakrishnan, L. (2014).Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs. J. Infect. Dis. 210, 456–466.10.1093/infdis/jiu095Search in Google Scholar PubMed PubMed Central
Apoorva, B., Nagatoshi, F., Kiranmai, B., Gurcha, S.S., Laurent, K., Bing, C., John, C., Porcelli, S.A., Kazuo, K., and Besra, G.S. (2007). Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and subclinical latent tuberculosis in immunocompetent mice. Proc. Natl. Acad. Sci. U.S.A. 104, 5157–5162.10.1073/pnas.0608654104Search in Google Scholar PubMed PubMed Central
Azad, A.K., Sirakova, T.D., Rogers, L.M., and Kolattukudy, P.E. (1996). Targeted replacement of the mycocerosic acid synthase gene in Mycobacterium bovis BCG produces a mutant that lacks mycosides. Proc. Natl. Acad. Sci. U.S.A. 93, 4787–4792.10.1073/pnas.93.10.4787Search in Google Scholar PubMed PubMed Central
Azad, A.K., Sirakova, T.D., Fernandes, N.D., and Kolattukudy, P.E. (1997). Gene knockout reveals a novel gene cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria. J. Biol. Chem. 272, 16741–16745.10.1074/jbc.272.27.16741Search in Google Scholar PubMed
Bailo, R., Bhatt, A., and Aínsa, J.A. (2015). Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development. Biochem. Pharmacol. 96, 159–167.10.1016/j.bcp.2015.05.001Search in Google Scholar PubMed
Bansal-Mutalik, R., and Nikaido, H. (2014). Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc. Natl. Acad. Sci. U.S.A. 111, 4958–4963.10.1073/pnas.1403078111Search in Google Scholar PubMed PubMed Central
Belardinelli, J.M., Larrouy-Maumus, G., Jones, V., de Carvalho, L.P.S., McNeil, M.R., and Jackson, M. (2014). Biosynthesis and translocation of unsulfated acyltrehaloses in Mycobacterium tuberculosis. J. Biol. Chem. 289, 27952–27965.10.1074/jbc.M114.581199Search in Google Scholar PubMed PubMed Central
Belisle, J.T., Vissa, V.D., Sievert, T., Takayama, K., Brennan, P.J., and Besra, G.S. (1997). Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276, 1420–1422.10.1126/science.276.5317.1420Search in Google Scholar PubMed
Benzaquen, L.R., Brugnara, C., Byers, H.R., Gattoni-Celli, S., and Halperin, J.A. (1995). Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat. Med. 1, 534–540.10.1038/nm0695-534Search in Google Scholar PubMed
Bernut, A., Viljoen, A., Dupont, C., Sapriel, G., Blaise, M., Bouchier, C., Brosch, R., de Chastellier, C., Herrmann, J.L., and Kremer, L. (2016). Insights into the smooth-to-rough transitioning in Mycobacterium bolletii unravels a functional Tyr residue conserved in all mycobacterial MmpL family members. Mol. Microbiol. 99, 866–883.10.1111/mmi.13283Search in Google Scholar PubMed
Besra, G.S., Sievert, T., Lee, R.E., Slayden, R.A., Brennan, P.J., and Takayama, K. (1994). Identification of the apparent carrier in mycolic acid synthesis. Proc. Natl. Acad. Sci. U.S.A. 91, 12735–12739.10.1073/pnas.91.26.12735Search in Google Scholar PubMed PubMed Central
Bhatt, A., Kremer, L., Dai, A.Z., Sacchettini, J.C., and Jacobs, W.R. (2005). Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis. J. Bacteriol. 187, 7596–7606.10.1128/JB.187.22.7596-7606.2005Search in Google Scholar PubMed PubMed Central
Bose, T., Das, C., Dutta, A., Mahamkali, V., Sadhu, S., and Mande, S.S. (2018). Understanding the role of interactions between host and Mycobacterium tuberculosis under hypoxic condition: an in silico approach. BMC Genomics 19, 555.10.1186/s12864-018-4947-8Search in Google Scholar PubMed PubMed Central
Brickman, T.J. and Armstrong, S.K. (2005). Bordetella AlcS transporter functions in alcaligin siderophore export and is central to inducer sensing in positive regulation of alcaligin system gene expression. J Bacteriol 187, 3650–3661.10.1128/JB.187.11.3650-3661.2005Search in Google Scholar PubMed PubMed Central
Briffotaux, J., Huang, W., Wang, X., and Gicquel, B. (2017). MmpS5/MmpL5 as an efflux pump in Mycobacterium species. Tuberculosis 107, 13–19.10.1016/j.tube.2017.08.001Search in Google Scholar PubMed
Brown, A.K., Apoorva, B., Albel, S., Elesh, S., Evans, A.F., and Besra, G.S. (2007). Identification of the dehydratase component of the mycobacterial mycolic acid-synthesizing fatty acid synthase-II complex. Microbiology 153, 4166–4173.10.1099/mic.0.2007/012419-0Search in Google Scholar PubMed
Brugnara, C., de Franceschi, L., and Alper, S.L. (1993). Inhibition of Ca2+-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J. Clin. Invest. 92, 520–526.10.1172/JCI116597Search in Google Scholar PubMed PubMed Central
Camacho, L.R., Ensergueix, D., Perez, E., Gicquel, B., and Guilhot, C. (1999). Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol. Microbiol. 34, 257–267.10.1046/j.1365-2958.1999.01593.xSearch in Google Scholar PubMed
Camacho, L.R., Constant, P., Raynaud, C., Lanéelle, M.-A., Triccas, J.A., Gicquel, B., Daffé, M., and Guilhot, C. (2001). Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis evidence that this lipid is involved in the cell wall permeability barrier. J. Biol. Chem. 276, 19845–19854.10.1074/jbc.M100662200Search in Google Scholar PubMed
Chalut, C. (2016). MmpL transporter-mediated export of cell-wall associated lipids and siderophores in mycobacteria. Tuberculosis 100, 32–45.10.1016/j.tube.2016.06.004Search in Google Scholar PubMed
Chesne-Seck, M.-L., Barilone, N., Boudou, F., Asensio, J.G., Kolattukudy, P.E., Martín, C., Cole, S.T., Gicquel, B., Gopaul, D.N., and Jackson, M. (2008). A point mutation in the two-component regulator PhoP-PhoR accounts for the absence of polyketide-derived acyltrehaloses but not that of phthiocerol dimycocerosates in Mycobacterium tuberculosis H37Ra. J. Bacteriol. 190, 1329–1334.10.1128/JB.01465-07Search in Google Scholar
Chim, N., Iniguez, A., Nguyen, T.Q., and Goulding, C.W. (2010). Unusual diheme conformation of the heme-degrading Protein from Mycobacterium tuberculosis. J. Mol. Biol. 395, 595–608.10.1016/j.jmb.2009.11.025Search in Google Scholar
Chim, N., Torres, R., Liu, Y., Capri, J., Batot, G., Whitelegge, J.P., and Goulding, C.W. (2015). The structure and interactions of periplasmic domains of crucial MmpL membrane proteins from Mycobacterium tuberculosis. Chem. Biol. 22, 1098–1107.10.1016/j.chembiol.2015.07.013Search in Google Scholar
Christian, H., Andrew, L., Michael, N., Plitzko, J.M., and Harald, E. (2008). Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc. Natl. Acad. Sci. U.S.A. 105, 3963–3967.10.1073/pnas.0709530105Search in Google Scholar
Cole, S., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S., Eiglmeier, K., Gas, S., and Barry Iii, C. (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544.10.1038/31159Search in Google Scholar
Converse, S.E., Mougous, J.D., Leavell, M.D., Leary, J.A., Bertozzi, C.R., and Cox, J.S. (2003). MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc. Natl. Acad. Sci. U.S.A. 100, 6121–6126.10.1073/pnas.1030024100Search in Google Scholar
Cox, J.S., Chen, B., McNeil, M., and Jacobs Jr., W.R. (1999). Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402, 79–83.10.1038/47042Search in Google Scholar
Daffé, M. and Draper, P. (1997). The envelope layers of mycobacteria with reference to their pathogenicity. Adv. Microb. Physiol. 39, 131–203.10.1016/S0065-2911(08)60016-8Search in Google Scholar
Daffé, M., Crick, D.C., and Jackson, M. (2014). Genetics of capsular polysaccharides and cell envelope (glyco)lipids. Microbiol. Spectr. 2, 1–46.10.1128/9781555818845.ch28Search in Google Scholar
Danelishvili, L., Chinison, J.J., Pham, T., Gupta, R., and Bermudez, L.E. (2017). The Voltage-Dependent Anion Channels (VDAC) of Mycobacterium avium phagosome are associated with bacterial survival and lipid export in macrophages. Sci. Rep. 7, 7007.10.1038/s41598-017-06700-3Search in Google Scholar PubMed PubMed Central
Delmar, J.A., Chou, T.-H., Wright, C.C., Licon, M.H., Doh, J.K., Radhakrishnan, A., Kumar, N., Lei, H.-T., Bolla, J.R., and Rajashankar, K.R. (2015). Structural basis for the regulation of the MmpL transporters of Mycobacterium tuberculosis. J. Biol. Chem. 290, 28559–28574.10.1074/jbc.M115.683797Search in Google Scholar PubMed PubMed Central
Deshayes, C., Bach, H., Euphrasie, D., Attarian, R., Coureuil, M., Sougakoff, W., Laval, F., Av-Gay, Y., Daffé, M., Etienne, G., et al. (2010). MmpS4 promotes glycopeptidolipids biosynthesis and export in Mycobacterium smegmatis. Mol. Microbiol. 78, 989–1003.10.1111/j.1365-2958.2010.07385.xSearch in Google Scholar PubMed
Domenech, P., Reed, M.B., Dowd, C.S., Manca, C., Kaplan, G., and Barry, C.E. (2004). The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis. J. Biol. Chem. 279, 21257–21265.10.1074/jbc.M400324200Search in Google Scholar PubMed
Domenech, P., Reed, M.B., and Barry, C.E. (2005). Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect. Immun. 73, 3492–3501.10.1128/IAI.73.6.3492-3501.2005Search in Google Scholar PubMed PubMed Central
Dubnau, E., Chan, J., Raynaud, C., Mohan, V.P., Lanéelle, M.A., Yu, K., Quémard, A., Smith, I., and Daffé, M. (2010). Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol. Microbiol. 36, 630–637.10.1046/j.1365-2958.2000.01882.xSearch in Google Scholar PubMed
Dubois, V., Viljoen, A., Laencina, L., Le Moigne, V., Bernut, A., Dubar, F., Blaise, M., Gaillard, J.-L., Guérardel, Y., and Kremer, L. (2018). MmpL8MAB controls Mycobacterium abscessus virulence and production of a previously unknown glycolipid family. Proc. Natl. Acad. Sci. U.S.A. 115, E10147–E10156.10.1073/pnas.1812984115Search in Google Scholar PubMed PubMed Central
Etienne, G., Malaga, W., Laval, F., Lemassu, A., Guilhot, C., and Daffé, M. (2009). Identification of the polyketide synthase involved in the biosynthesis of the surface-exposed lipooligosaccharides in mycobacteria. J. Bacteriol. 191, 2613–2621.10.1128/JB.01235-08Search in Google Scholar PubMed PubMed Central
Fang, X., Wallqvist, A., and Reifman, J. (2012). Modeling phenotypic metabolic adaptations of Mycobacterium tuberculosis H37Rv under hypoxia. PLoS Comput. Biol. 8, e1002688.10.1371/journal.pcbi.1002688Search in Google Scholar PubMed PubMed Central
Fay, A., Czudnochowski, N., Rock, J.M., Johnson, J.R., Krogan, N.J., Rosenberg, O., and Glickman, M.S. (2019). Two accessory proteins govern MmpL3 mycolic acid transport in mycobacteria. MBio 10, e00850-19.10.1128/mBio.00850-19Search in Google Scholar PubMed PubMed Central
Galagan, J.E., Minch, K., Peterson, M., Lyubetskaya, A., Azizi, E., Sweet, L., Gomes, A., Rustad, T., Dolganov, G., and Glotova, I. (2013). The Mycobacterium tuberculosis regulatory network and hypoxia. Nature 499, 178–183.10.1038/nature12337Search in Google Scholar PubMed PubMed Central
Gannoun-Zaki, L., Alibaud, L., Carrère-Kremer, S., Kremer, L., and Blanc-Potard, A.-B. (2013). Overexpression of the KdpF membrane peptide in Mycobacterium bovis BCG results in reduced intramacrophage growth and altered cording morphology. PLoS One 8, e60379.10.1371/journal.pone.0060379Search in Google Scholar
Glickman, M.S., Cox, J.S., and Jacobs Jr, W.R. (2000). A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol. Cell. 5, 717–727.10.1016/S1097-2765(00)80250-6Search in Google Scholar
Goren, M.B. (1970). Sulfolipid I of Mycobacterium tuberculosis, strain H37Rv. I. Purification and properties. Biochim. Biophys. Acta 210, 116–126.10.1016/0005-2760(70)90067-6Search in Google Scholar
Goren, M.B., Brokl, O., Das, B.C., and Lederer, E. (1971). Sulfolipid I of Mycobacterium tuberculosis, strain H37RV. Nature of the acyl substituents. Biochemistry 10, 72–81.10.1021/bi00777a012Search in Google Scholar PubMed
Goren, M.B., D’Arcy, H.P., Young, M.R., and Armstrong, J.A. (1976). Prevention of phagosome-lysosome fusion in cultured macrophages by sulfatides of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U.S.A. 73, 2510–2514.10.1073/pnas.73.7.2510Search in Google Scholar PubMed PubMed Central
Grzegorzewicz, A.E., Pham, H., Gundi, V.A., Scherman, M.S., North, E.J., Hess, T., Jones, V., Gruppo, V., Born, S.E., and Korduláková, J. (2012). Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat. Chem. Biol. 8, 334–341.10.1038/nchembio.794Search in Google Scholar PubMed PubMed Central
Halloum, I., Viljoen, A., Khanna, V., Craig, D., Bouchier, C., Brosch, R., Coxon, G., and Kremer, L. (2017). Resistance to thiacetazone derivatives active against Mycobacterium abscessus involves mutations in the MmpL5 transcriptional repressor MAB_4384. Antimicrob. Agents Chemother. 61, 02509–02516.10.1128/AAC.02509-16Search in Google Scholar PubMed PubMed Central
Hartkoorn, R.C., Swapna, U., and Cole, S.T. (2014). Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 58, 2979–2981.10.1128/AAC.00037-14Search in Google Scholar PubMed PubMed Central
Hatzios, S.K., Schelle, M.W., Holsclaw, C.M., Behrens, C.R., Botyanszki, Z., Lin, F.L., Carlson, B.L., Kumar, P., Leary, J.A., and Bertozzi, C.R. (2009). PapA3 is an acyltransferase required for polyacyltrehalose biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 284, 12745–12751.10.1074/jbc.M809088200Search in Google Scholar PubMed PubMed Central
Jain, M. and Cox, J.S. (2005). Interaction between polyketide synthase and transporter suggests coupled synthesis and export of virulence lipid in M. tuberculosis. PLoS Pathog. 1, e2.10.1371/journal.ppat.0010002Search in Google Scholar PubMed PubMed Central
Jones, C.M., Wells, R.M., Madduri, A.V., Renfrow, M.B., Ratledge, C., Moody, D.B., and Niederweis, M.(2014). Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling. Proc. Natl. Acad. Sci. U.S.A. 111, 1945–1950.10.1073/pnas.1311402111Search in Google Scholar
Kaufmann, S.H., Lange, C., Rao, M., Balaji, K.N., Lotze, M., Schito, M., Zumla, A.I., and Maeurer, M. (2014). Progress in tuberculosis vaccine development and host-directed therapies–a state of the art review. Lancet Respir. Med. 2, 301–320.10.1016/S2213-2600(14)70033-5Search in Google Scholar
Korycka-Machała, M., Viljoen, A., Pawełczyk, J., Borówka, P., Dziadek, B., Gobis, K., Brzostek, A., Kawka, M., Blaise, M., and Strapagiel, D. (2019). 1H-benzo [d] imidazole derivatives affect MmpL3 in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. AAC, 00441–00419. doi: https://doi.org/10.1128/AAC.00441-19.10.1128/AAC.00441-19Search in Google Scholar PubMed PubMed Central
La Rosa, V., Poce, G., Canseco, J.O., Buroni, S., Pasca, M.R., Biava, M., Raju, R.M., Porretta, G.C., Alfonso, S., and Battilocchio, C. (2012). MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob. Agents Chemother 56, 324–331.10.1128/AAC.05270-11Search in Google Scholar PubMed PubMed Central
Lamichhane, G., Tyagi, S., and Bishai, W.R. (2005). Designer arrays for defined mutant analysis to detect genes essential for survival of Mycobacterium tuberculosis in mouse lungs. Infect. Immun. 73, 2533–2540.10.1128/IAI.73.4.2533-2540.2005Search in Google Scholar PubMed PubMed Central
Laurent, K., Chantal, D.C., Gary, D., Gibson, K.J.C., Pablo, B., Stéphanie, B., Jean-Pierre, G., Camille, L., Minnikin, D.E., and Besra, G.S. (2010). Identification and structural characterization of an unusual mycobacterial monomeromycolyl-diacylglycerol. Mol. Microbiol. 57, 1113–1126.Search in Google Scholar
Li, W., Upadhyay, A., Fontes, F.L., North, E.J., Wang, Y., Crans, D.C., Grzegorzewicz, A.E., Jones, V., Franzblau, S.G., and Lee, R.E. (2014). Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 58, 6413–6423.10.1128/AAC.03229-14Search in Google Scholar PubMed PubMed Central
Lubelski, J., Konings, W.N., and Driessen, A.J. (2007). Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria. Microbiol. Mol. Biol. Rev. 71, 463–476.10.1128/MMBR.00001-07Search in Google Scholar PubMed PubMed Central
Madigan, C.A., Cheng, T.Y., Layre, E., Young, D.C., McConnell, M.J., Debono, C.A., Murry, J.P., Wei, J.R., Barry, C.E., Rodriguez, G.M., et al. (2012). Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U.S.A. 109, 1257–1262.10.1073/pnas.1109958109Search in Google Scholar PubMed PubMed Central
Marrakchi, H., Lanéelle, M.A., and Daffé, M. (2013). Mycolic acids: structures, biosynthesis, and beyond. Chem. Biol. 21, 67–85.10.1016/j.chembiol.2013.11.011Search in Google Scholar PubMed
Milano, A., Pasca, M.R., Provvedi, R., Lucarelli, A.P., Manina, G., Ribeiro, A.L., Manganelli, R., and Riccardi, G. (2009). Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5–MmpL5 efflux system. Tuberculosis 89, 84–90.10.1016/j.tube.2008.08.003Search in Google Scholar PubMed
Muñoz-Planillo, R., Kuffa, P., Martínez-Colón, G., Smith, B.L., Rajendiran, T.M., and Núñez, G. (2013). K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153.10.1016/j.immuni.2013.05.016Search in Google Scholar PubMed PubMed Central
Nikaido, H. (2011). Structure and mechanism of RND-type multidrug efflux pumps. Adv. Enzymol. Relat. Areas Mol. Biol. 77, 1–60.10.1002/9780470920541.ch1Search in Google Scholar PubMed PubMed Central
Nikaido, H. and Zgurskaya, H.I. (2001). AcrAB and related multidrug efflux pumps of Escherichia coli. J. Mol. Microb. Biotech. 3, 215–218.Search in Google Scholar
North, R.J., Ryan, L., Lacource, R., Mogues, T., and Goodrich, M.E. (1999). Growth rate of mycobacteria in mice as an unreliable indicator of mycobacterial virulence. Infect. Immun. 67, 5483–5485.10.1128/IAI.67.10.5483-5485.1999Search in Google Scholar PubMed PubMed Central
Onwueme, K.C., Ferreras, J.A., Buglino, J., Lima, C.D., and Quadri, L.E. (2004). Mycobacterial polyketide-associated proteins are acyltransferases: proof of principle with Mycobacterium tuberculosis PapA5. Proc. Natl. Acad. Sci. U.S.A. 101, 4608–4613.10.1073/pnas.0306928101Search in Google Scholar PubMed PubMed Central
Pacheco, S.A., Hsu, F.-F., Powers, K.M., and Purdy, G.E. (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, 24213–24222.10.1074/jbc.M113.473371Search in Google Scholar PubMed PubMed Central
Pasca, M.R., Guglierame, P., Rossi, E.D., Zara, F., and Riccardi, A. (2005). mmpL7 Gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob. Agents Chemother. 49, 4775–4777.10.1128/AAC.49.11.4775-4777.2005Search in Google Scholar PubMed PubMed Central
Patin, E.C., Geffken, A.C., Willcocks, S., Leschczyk, C., Haas, A., Nimmerjahn, F., Lang, R., Ward, T.H., and Schaible, U.E. (2017). Trehalose dimycolate interferes with FcγR-mediated phagosome maturation through Mincle, SHP-1 and FcγRIIB signalling. PLoS One 12, e0174973.10.1371/journal.pone.0174973Search in Google Scholar PubMed PubMed Central
Pérez, J., Garcia, R., Bach, H., de Waard, J.H., Jacobs Jr, W.R., Av-Gay, Y., Bubis, J., and Takiff, H.E. (2006). Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. Biochem. Biophs. Res. Commun. 348, 6–12.10.1016/j.bbrc.2006.06.164Search in Google Scholar PubMed
Pilar, D., Reed, M.B., and Barry, C.E. (2005). Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect. Immun. 73, 3492–3501.10.1128/IAI.73.6.3492-3501.2005Search in Google Scholar PubMed PubMed Central
Poce, G., Bates, R.H., Alfonso, S., Cocozza, M., Porretta, G.C., Ballell, L., Rullas, J., Ortega, F., De Logu, A., and Agus, E. (2013). Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS One 8, e56980.10.1371/journal.pone.0056980Search in Google Scholar PubMed PubMed Central
Poole, K. (2001). Multidrug efflux pumps and antimicrobial resistance in Pseudomonas aeruginosa and related organisms. J. Mol. Microb. Biotech. 3, 255–264.Search in Google Scholar
Poole, K., Tetro, K., Zhao, Q., Neshat, S., Heinrichs, D.E., and Bianco, N. (1996). Expression of the multidrug resistance operon mexA-mexB-oprM in Pseudomonas aeruginosa: mexR encodes a regulator of operon expression. Antimicrob. Agents Chemother. 40, 2021–2028.10.1128/AAC.40.9.2021Search in Google Scholar PubMed PubMed Central
Puech, V., Guilhot, C., Perez, E., Tropis, M., Armitige, L.Y., Gicquel, B., and Daffé, M. (2002). Evidence for a partial redundancy of the fibronectin-binding proteins for the transfer of mycoloyl residues onto the cell wall arabinogalactan termini of Mycobacterium tuberculosis. Mol. Microbiol. 44, 1109–1122.10.1046/j.1365-2958.2002.02953.xSearch in Google Scholar PubMed
Purdy, G.E., Michael, N., and Russell, D.G. (2010). Decreased outer membrane permeability protects mycobacteria from killing by ubiquitin-derived peptides. Mol. Microbiol. 73, 844–857.10.1111/j.1365-2958.2009.06801.xSearch in Google Scholar PubMed PubMed Central
Radhakrishnan, A., Kumar, N., Wright, C.C., Chou, T.-H., Tringides, M.L., Bolla, J.R., Lei, H.-T., Rajashankar, K.R., Su, C.-C., and Purdy, G.E. (2014). Crystal structure of the transcriptional regulator Rv0678 of Mycobacterium tuberculosis. J. Biol. Chem. 289, 16526–16540.10.1074/jbc.M113.538959Search in Google Scholar PubMed PubMed Central
Rao, S.P., Lakshminarayana, S.B., Kondreddi, R.R., Herve, M., Camacho, L.R., Bifani, P., Kalapala, S.K., Jiricek, J., Ma, N.L., and Tan, B.H. (2013). Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Sci. Transl. Med. 5, 214ra168.10.1126/scitranslmed.3007355Search in Google Scholar PubMed
Remuiñán, M.J., Pérez-Herrán, E., Rullás, J., Alemparte, C., Martínez-Hoyos, M., Dow, D.J., Afari, J., Mehta, N., Esquivias, J., and Jiménez, E. (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, e60933.10.1371/journal.pone.0060933Search in Google Scholar PubMed PubMed Central
Richard, M., Gutierrez, A.V., Viljoen, A., Rodriguez-Rincon, D., Roquet-Baneres, F., Blaise, M., Everall, I., Parkhill, J., Floto, R.A., and Kremer, L. (2019). Mutations in the MAB_2299c TetR regulator confer cross-resistance to Clofazimine and Bedaquiline in Mycobacterium abscessus. Antimicrob. Agents Chemother. 63, e01316-18. doi: https://doi.org/10.1128/AAC.01316-18.10.1128/AAC.01316-18Search in Google Scholar PubMed PubMed Central
Rodrigues, L., Machado, D., Couto, I., Amaral, L., and Viveiros, M. (2012). Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect. Genet. Evol. 12, 695–700.10.1016/j.meegid.2011.08.009Search in Google Scholar PubMed
Rodriguez, G.M. and Smith, I. (2006). Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J. Bacteriol. 188, 424–430.10.1128/JB.188.2.424-430.2006Search in Google Scholar PubMed PubMed Central
Rossi, E.D., Aínsa, J.A., and Riccardi, G. (2006). Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol. Rev. 30, 36–52.10.1111/j.1574-6976.2005.00002.xSearch in Google Scholar PubMed
Ryndak, M.B., Wang, S., Smith, I., and Rodriguez, G.M. (2010). The Mycobacterium tuberculosis high-affinity iron importer, IrtA, contains an FAD-binding domain. J. Bacteriol. 192, 861–869.10.1128/JB.00223-09Search in Google Scholar PubMed PubMed Central
Sandhu, P. and Akhter, Y. (2015). The internal gene duplication and interrupted coding sequences in the MmpL genes of Mycobacterium tuberculosis: towards understanding the multidrug transport in an evolutionary perspective. Int. J. Med. Microbiol. 305, 413–423.10.1016/j.ijmm.2015.03.005Search in Google Scholar PubMed
Seeliger, J.C., Holsclaw, C.M., Schelle, M.W., Botyanszki, Z., Gilmore, S.A., Tully, S.E., Niederweis, M., Cravatt, B.F., Leary, J.A., and Bertozzi, C.R. (2012). Elucidation and chemical modulation of sulfolipid-1 biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 287, 7990–8000.10.1074/jbc.M111.315473Search in Google Scholar PubMed PubMed Central
Shuishu, W., Jean, E.N., and Issar, S. (2007). Structure of the DNA-binding domain of the response regulator PhoP from Mycobacterium tuberculosis. Biochemistry 46, 14751–14761.10.1021/bi700970aSearch in Google Scholar PubMed PubMed Central
Sirakova, T.D., Thirumala, A.K., Dubey, V.S., Sprecher, H., and Kolattukudy, P.E. (2001). The Mycobacterium tuberculosis pks2 gene encodes the synthase for the hepta- and octamethyl-branched fatty acids required for sulfolipid synthesis. J. Biol. Chem. 276, 16833–16839.10.1074/jbc.M011468200Search in Google Scholar PubMed
Snider, D., Raviglione, M., Kochi, A., and Bloom, B. (1994). Tuberculosis: pathogenesis, protection, and control. Am. Soc. Microbiol. USA 29, 1054.Search in Google Scholar
Song, L. and Wu, X. (2016). Development of efflux pump inhibitors in antituberculosis therapy. Int. J. Antimicrob. Agents 47, 421–429.10.1016/j.ijantimicag.2016.04.007Search in Google Scholar PubMed
Stanley, S.A., Grant, S.S., Kawate, T., Iwase, N., Shimizu, M., Wivagg, C., Silvis, M., Kazyanskaya, E., Aquadro, J., and Golas, A. (2012). Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. ACS Chem. Biol. 7, 1377–1384.10.1021/cb300151mSearch in Google Scholar PubMed PubMed Central
Strong, E.J. and West, N.P. (2018). Use of soluble extracellular regions of MmpL (SERoM) as vaccines for tuberculosis. Sci. Rep. 8, 5604.10.1038/s41598-018-23893-3Search in Google Scholar PubMed PubMed Central
Sulzenbacher, G., Canaan, S., Bordat, Y., Neyrolles, O., Stadthagen, G., Roig-Zamboni, V., Rauzier, J., Maurin, D., Laval, F., and Daffé, M. (2006). LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to the surface of Mycobacterium tuberculosis. EMBO J. 25, 1436–1444.10.1038/sj.emboj.7601048Search in Google Scholar PubMed PubMed Central
Tahlan, K., Wilson, R., Kastrinsky, D.B., Arora, K., Nair, V., Fischer, E., Barnes, S.W., Walker, J.R., Alland, D., and Barry, C.E. (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, 1797–1809.10.1128/AAC.05708-11Search in Google Scholar PubMed PubMed Central
Tekaia, F., Gordon, S.V., Garnier, T., Brosch, R., Barrell, B.G., and Cole, S.T. (1999). Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber. Lung Dis. 79, 329–342.10.1054/tuld.1999.0220Search in Google Scholar PubMed
Trivedi, O.A., Arora, P., Sridharan, V., Tickoo, R., Mohanty, D., and Gokhale, R.S. (2004). Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 428, 441–445.10.1038/nature02384Search in Google Scholar PubMed
Trivedi, O.A., Arora, P., Vats, A., Ansari, M.Z., Tickoo, R., Sridharan, V., Mohanty, D., and Gokhale, R.S. (2005). Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid. Mol. Cell. 17, 631–643.10.1016/j.molcel.2005.02.009Search in Google Scholar PubMed
Tseng, T.-T., Gratwick, K.S., Kollman, J., Park, D., Nies, D.H., Goffeau, A., and Saier Jr, M.H. (1999). The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microb. Biotech. 1, 107–125.Search in Google Scholar
Tullius, M.V., Harmston, C.A., Owens, C.P., Chim, N., Morse, R.P., McMath, L.M., Iniguez, A., Kimmey, J.M., Sawaya, M.R., and Whitelegge, J.P. (2011). Discovery and characterization of a unique mycobacterial heme acquisition system. Proc. Natl. Acad. Sci. U.S.A. 108, 5051–5056.10.1073/pnas.1009516108Search in Google Scholar PubMed PubMed Central
Varela, C., Rittmann, D., Singh, A., Krumbach, K., Bhatt, K., Eggeling, L., Besra, G., and Bhatt, A. (2012). MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem. Biol. 19, 498–506.10.1016/j.chembiol.2012.03.006Search in Google Scholar PubMed PubMed Central
Vilchèze, C., Morbidoni, H.R., Weisbrod, T.R., Iwamoto, H., Kuo, M., Sacchettini, J.C., and Jacobs, W.R. (2000). Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J. Bacteriol. 182, 4059–4067.10.1128/JB.182.14.4059-4067.2000Search in Google Scholar PubMed PubMed Central
Viljoen, A., Dubois, V., Girard-Misguich, F., Blaise, M., Herrmann, J.L., and Kremer, L. (2017). The diverse family of M mp L transporters in mycobacteria: from regulation to antimicrobial developments. Mol. Microbiol. 104, 889–904.10.1111/mmi.13675Search in Google Scholar PubMed
Wells, R.M., Jones, C.M., Xi, Z., Speer, A., Danilchanka, O., Doornbos, K.S., Sun, P., Wu, F., Tian, C., and Niederweis, M. (2013). Discovery of a siderophore export system essential for virulence of Mycobacterium tuberculosis. PLoS Pathog. 9, e1003120.10.1371/journal.ppat.1003120Search in Google Scholar PubMed PubMed Central
Williams, E.P., Lee, J.-H., Bishai, W.R., Colantuoni, C., and Karakousis, P.C. (2007). Mycobacterium tuberculosis SigF regulates genes encoding cell wall-associated proteins and directly regulates the transcriptional regulatory gene phoY1. J. Bacteriol. 189, 4234–4242.10.1128/JB.00201-07Search in Google Scholar PubMed PubMed Central
World Health Organization (2018). Global tuberculosis report 2018. World Health Organization.Search in Google Scholar
Wright, C.C., Hsu, F.F., Arnett, E., Dunaj, J.L., Davidson, P.M., Pacheco, S.A., Harriff, M.J., Lewinsohn, D.M., Schlesinger, L.S., and Purdy, G.E. (2017). The Mycobacterium tuberculosis MmpL11 cell wall lipid transporter is important for biofilm formation, intracellular growth, and nonreplicating persistence. Infect. Immun. 85, e00131–00117.10.1128/IAI.00131-17Search in Google Scholar PubMed PubMed Central
Wu, S.-N., Li, H.-F., Jan, C.-R., and Shen, A.-Y. (1999). Inhibition of Ca2+-activated K+ current by clotrimazole in rat anterior pituitary GH3 cells. Neuropharmacology 38, 979–989.10.1016/S0028-3908(99)00027-1Search in Google Scholar
Xu, Z., Meshcheryakov, V.A., Poce, G., and Chng, S.-S. (2017). MmpL3 is the flippase for mycolic acids in mycobacteria. Proc. Natl. Acad. Sci. U.S.A. 114, 7993–7998.10.1073/pnas.1700062114Search in Google Scholar PubMed PubMed Central
Zhang, H., Li, D., Zhao, L., Fleming, J., Lin, N., Wang, T., Liu, Z., Li, C., Galwey, N., and Deng, J. (2013). Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance. Nat. Genet. 45, 1255–1260.10.1038/ng.2735Search in Google Scholar PubMed
Zhang, B., Li, J., Yang, X., Wu, L., Zhang, J., Yang, Y., Zhao, Y., Zhang, L., Yang, X., and Yang, X. (2019). Crystal structures of membrane transporter MmpL3, an anti-TB drug target. Cell 176, 636–648. e613.10.1016/j.cell.2019.01.003Search in Google Scholar PubMed
Zuber, B., Chami, M., Houssin, C., Dubochet, J., Griffiths, G., and Daffé, M. (2008). Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J. Bacteriol. 190, 5672–5680.10.1128/JB.01919-07Search in Google Scholar PubMed PubMed Central
©2020 Walter de Gruyter GmbH, Berlin/Boston