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Role of the lipid bilayer in outer membrane protein folding in Gram-negative bacteria

2020; Elsevier BV; Volume: 295; Issue: 30 Linguagem: Inglês

10.1074/jbc.rev120.011473

ISSN

1083-351X

Autores

Jim E. Horne, David J. Brockwell, Sheena E. Radford,

Tópico(s)

Antibiotic Resistance in Bacteria

Resumo

β-Barrel outer membrane proteins (OMPs) represent the major proteinaceous component of the outer membrane (OM) of Gram-negative bacteria. These proteins perform key roles in cell structure and morphology, nutrient acquisition, colonization and invasion, and protection against external toxic threats such as antibiotics. To become functional, OMPs must fold and insert into a crowded and asymmetric OM that lacks much freely accessible lipid. This feat is accomplished in the absence of an external energy source and is thought to be driven by the high thermodynamic stability of folded OMPs in the OM. With such a stable fold, the challenge that bacteria face in assembling OMPs into the OM is how to overcome the initial energy barrier of membrane insertion. In this review, we highlight the roles of the lipid environment and the OM in modulating the OMP-folding landscape and discuss the factors that guide folding in vitro and in vivo. We particularly focus on the composition, architecture, and physical properties of the OM and how an understanding of the folding properties of OMPs in vitro can help explain the challenges they encounter during folding in vivo. Current models of OMP biogenesis in the cellular environment are still in flux, but the stakes for improving the accuracy of these models are high. OMP folding is an essential process in all Gram-negative bacteria, and considering the looming crisis of widespread microbial drug resistance it is an attractive target. To bring down this vital OMP-supported barrier to antibiotics, we must first understand how bacterial cells build it. β-Barrel outer membrane proteins (OMPs) represent the major proteinaceous component of the outer membrane (OM) of Gram-negative bacteria. These proteins perform key roles in cell structure and morphology, nutrient acquisition, colonization and invasion, and protection against external toxic threats such as antibiotics. To become functional, OMPs must fold and insert into a crowded and asymmetric OM that lacks much freely accessible lipid. This feat is accomplished in the absence of an external energy source and is thought to be driven by the high thermodynamic stability of folded OMPs in the OM. With such a stable fold, the challenge that bacteria face in assembling OMPs into the OM is how to overcome the initial energy barrier of membrane insertion. In this review, we highlight the roles of the lipid environment and the OM in modulating the OMP-folding landscape and discuss the factors that guide folding in vitro and in vivo. We particularly focus on the composition, architecture, and physical properties of the OM and how an understanding of the folding properties of OMPs in vitro can help explain the challenges they encounter during folding in vivo. Current models of OMP biogenesis in the cellular environment are still in flux, but the stakes for improving the accuracy of these models are high. OMP folding is an essential process in all Gram-negative bacteria, and considering the looming crisis of widespread microbial drug resistance it is an attractive target. To bring down this vital OMP-supported barrier to antibiotics, we must first understand how bacterial cells build it. Proteins that span lipid bilayers come in two types, either α-helical or β-barrels. Whereas the cytosolic inner membranes (IMs) of bacteria and the plasma membrane of eukaryotes are comprised only of α-helical membrane proteins, β-barrel outer membrane proteins (OMPs) are found exclusively in the outer membranes (OMs) of diderm bacteria as well as in bacterially derived eukaryotic organelles, such as mitochondria and chloroplasts. The “OMPome” (the complement of OMPs encoded for by a genome) of Escherichia coli consists of a large number of proteins ranging in barrel size from 8 to 26 β-strands and includes monomers, small assemblies (dimers, trimers etc.), and oligomeric structures that can form up to 60-stranded pores (Fig. 1). Some OMPs comprise only the integral membrane β-barrel structure, whereas others have soluble domains in the periplasm or on the extracellular surface of the OM. Some OMPs have low copy number or can be absent in the OM under “standard” growth conditions (e.g. the E. coli porin OmpN) (1Prilipov A. Phale P.S. Koebnik R. Widmer C. Rosenbusch J.P. Identification and characterization of two quiescent porin genes, nmpC ompN, in Escherichia coli BE.J. Bacteriol. 1998; 180 (9642192): 3388-339210.1128/JB.180.13.3388-3392.1998Crossref PubMed Google Scholar, 2Fàbrega A. Rosner J.L. Martin R.G. Solé M. Vila J. SoxS-dependent coregulation of ompN ydbK in a multidrug-resistant Escherichia coli strain.FEMS Microbiol. Lett. 2012; 332 (22515487): 61-6710.1111/j.1574-6968.2012.02577.xCrossref PubMed Scopus (6) Google Scholar, 3Li G.-W. Burkhardt D. Gross C. Weissman J.S. Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources.Cell. 2014; 157 (24766808): 624-63510.1016/j.cell.2014.02.033Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar, 4Soufi B. Krug K. Harst A. Macek B. Characterization of the E. coli proteome and its modifications during growth and ethanol stress.Front. Microbiol. 2015; 6 (25741329): 10310.3389/fmicb.2015.00103Crossref PubMed Scopus (66) Google Scholar), and others are present in large copy number (e.g. OmpA is estimated to have >100,000 copies in the OM of E. coli, whereas OmpX, OmpC, and OmpF are estimated to have >20,000 copies each) (3Li G.-W. Burkhardt D. Gross C. Weissman J.S. Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources.Cell. 2014; 157 (24766808): 624-63510.1016/j.cell.2014.02.033Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar, 4Soufi B. Krug K. Harst A. Macek B. Characterization of the E. coli proteome and its modifications during growth and ethanol stress.Front. Microbiol. 2015; 6 (25741329): 10310.3389/fmicb.2015.00103Crossref PubMed Scopus (66) Google Scholar, 5Henning U. Höhn B. Sonntag I. Cell envelope and shape of Escherichia coli K12: the ghost membrane.Eur. J. Biochem. 1973; 39 (4589028): 27-3610.1111/j.1432-1033.1973.tb03099.xCrossref PubMed Google Scholar, 6Rosenbusch J.P. Characterization of the major envelope protein from Escherichia coli. Regular arrangement on the peptidoglycan and unusual dodecyl sulfate binding.J. Biol. Chem. 1974; 249 (4609976): 8019-8029Abstract Full Text PDF PubMed Google Scholar, 7Lugtenberg B. Van Alphen L. Molecular architecture and functioning of the outer membrane of Escherichia coli and other Gram-negative bacteria.Biochim. Biophys. Acta. 1983; 737 (6337630): 51-11510.1016/0304-4157(83)90014-XCrossref PubMed Scopus (463) Google Scholar). The functions of OMPs are also very diverse, including passive pores and ion channels (8Ye J. van den Berg B. Crystal structure of the bacterial nucleoside transporter Tsx.EMBO J. 2004; 23 (15272310): 3187-319510.1038/sj.emboj.7600330Crossref PubMed Scopus (87) Google Scholar, 9Subbarao G.V. van den Berg B. Crystal structure of the monomeric porin OmpG.J. Mol. Biol. 2006; 360 (16797588): 750-75910.1016/j.jmb.2006.05.045Crossref PubMed Scopus (85) Google Scholar, 10Wirth C. Condemine G. Boiteux C. Bernèche S. Schirmer T. Peneff C.M. NanC crystal structure, a model for outer-membrane channels of the acidic sugar-specific KdgM porin family.J. Mol. Biol. 2009; 394 (19796645): 718-73110.1016/j.jmb.2009.09.054Crossref PubMed Scopus (28) Google Scholar, 11Vergalli J. Bodrenko I.V. Masi M. Moynié L. Acosta-Gutiérrez S. Naismith J.H. Davin-Regli A. Ceccarelli M. van den Berg B. Winterhalter M. Pagès J.-M. Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria.Nat. Rev. Microbiol. 2019; 18 (31792365): 164-17610.1038/s41579-019-0294-2Crossref PubMed Scopus (18) Google Scholar), antibiotic efflux channels (12Xu C. Lin X. Ren H. Zhang Y. Wang S. Peng X. Analysis of outer membrane proteome of Escherichia coli related to resistance to ampicillin and tetracycline.Proteomics. 2006; 6 (16372265): 462-47310.1002/pmic.200500219Crossref PubMed Scopus (99) Google Scholar, 13Beketskaia M.S. Bay D.C. Turner R.J. Outer membrane protein OmpW participates with small multidrug resistance protein member EmrE in quaternary cationic compound efflux.J. Bacteriol. 2014; 196 (24633876): 1908-191410.1128/JB.01483-14Crossref PubMed Scopus (26) Google Scholar, 14Wang Z. Fan G. Hryc C.F. Blaza J.N. Serysheva I.I. Schmid M.F. Chiu W. Luisi B.F. Du D. An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump.Elife. 2017; 6 (28355133): e2490510.7554/eLife.24905Crossref PubMed Scopus (86) Google Scholar, 15Fitzpatrick A.W.P. Llabrés S. Neuberger A. Blaza J.N. Bai X.-C. Okada U. Murakami S. van Veen H.W. Zachariae U. Scheres S.H.W. Luisi B.F. Du D. Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump.Nat. Microbiol. 2017; 2 (28504659): 1707010.1038/nmicrobiol.2017.70Crossref PubMed Scopus (66) Google Scholar), nutrient uptake systems (16Noinaj N. Guillier M. Barnard T.J. Buchanan S.K. TonB-dependent transporters: regulation, structure, and function.Annu. Rev. Microbiol. 2010; 64 (20420522): 43-6010.1146/annurev.micro.112408.134247Crossref PubMed Scopus (480) Google Scholar, 17Lepore B.W. Indic M. Pham H. Hearn E.M. Patel D.R. van den Berg B. Ligand-gated diffusion across the bacterial outer membrane.Proc. Natl. Acad. Sci. U. S. A. 2011; 108 (21593406): 10121-1012610.1073/pnas.1018532108Crossref PubMed Scopus (50) Google Scholar, 18Aunkham A. Zahn M. Kesireddy A. Pothula K.R. Schulte A. Baslé A. Kleinekathöfer U. Suginta W. van den Berg B. Structural basis for chitin acquisition by marine Vibrio species.Nat. Commun. 2018; 9 (29335469): 22010.1038/s41467-017-02523-yCrossref PubMed Scopus (14) Google Scholar), maintenance of structural integrity (19Rojas E.R. Billings G. Odermatt P.D. Auer G.K. Zhu L. Miguel A. Chang F. Weibel D.B. Theriot J.A. Huang K.C. The outer membrane is an essential load-bearing element in Gram-negative bacteria.Nature. 2018; 559 (30022160): 617-62110.1038/s41586-018-0344-3Crossref PubMed Scopus (120) Google Scholar, 20Samsudin F. Ortiz-Suarez M.L. Piggot T.J. Bond P.J. Khalid S. OmpA: a flexible clamp for bacterial cell wall attachment.Structure. 2016; 24 (27866852): 2227-223510.1016/j.str.2016.10.009Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 21Vollmer W. Von Rechenberg M. Höltje J.V. Demonstration of molecular interactions between the murein polymerase PBP1B, the lytic transglycosylase MltA, and the scaffolding protein MipA of Escherichia coli.J. Biol. Chem. 1999; 274 (10037771): 6726-673410.1074/jbc.274.10.6726Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), biogenesis and upkeep of the OM (22Braun M. Silhavy T.J. Imp/OstA is required for cell envelope biogenesis in Escherichia coli.Mol. Microbiol. 2002; 45 (12207697): 1289-130210.1046/j.1365-2958.2002.03091.xCrossref PubMed Scopus (178) Google Scholar, 23Voulhoux R. Bos M.P. Geurtsen J. Mols M. Tommassen J. Role of a highly conserved bacterial protein in outer membrane protein assembly.Science. 2003; 299 (12522254): 262-26510.1126/science.1078973Crossref PubMed Scopus (545) Google Scholar, 24Bishop R.E. Gibbons H.S. Guina T. Trent M.S. Miller S.I. Raetz C.R.H. Transfer of palmitate from phospholipids to lipid A in outer membranes of Gram-negative bacteria.EMBO J. 2000; 19 (11013210): 5071-508010.1093/emboj/19.19.5071Crossref PubMed Google Scholar, 25May K.L. Silhavy T.J. The Escherichia coli phospholipase PldA regulates outer membrane homeostasis via lipid signaling.MBio. 2018; 9 (29559571): 11325-1134010.1128/mBio.00379-18Google Scholar, 26Stubenrauch C.J. Lithgow T. The TAM: a translocation and assembly module of the β-barrel assembly machinery in bacterial outer membranes.EcoSal Plus. 2019; 8 (30816086)10.1128/ecosalplus.ESP-0036-2018PubMed Google Scholar), host cell adhesion and invasion (27Mecsas J. Welch R. Erickson J.W. Gross C.A. Identification and characterization of an outer membrane protein, OmpX, in Escherichia coli that is homologous to a family of outer membrane proteins including Ail of Yersinia enterocolitica.J. Bacteriol. 1995; 177 (7836315): 799-80410.1128/jb.177.3.799-804.1995Crossref PubMed Google Scholar, 28Mulvey M.A. Lopez-Boado Y.S. Wilson C.L. Roth R. Parks W.C. Heuser J. Hultgren S.J. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli.Science. 1998; 282 (9822381): 1494-149710.1126/science.282.5393.1494Crossref PubMed Google Scholar, 29Du M. Yuan Z. Yu H. Henderson N. Sarowar S. Zhao G. Werneburg G.T. Thanassi D.G. Li H. Handover mechanism of the growing pilus by the bacterial outer-membrane usher FimD.Nature. 2018; 562 (30283140): 444-44710.1038/s41586-018-0587-zCrossref PubMed Scopus (10) Google Scholar), biofilm formation (30Henderson I.R. Owen P. The major phase-variable outer membrane protein of Escherichia coli structurally resembles the immunoglobulin A1 protease class of exported protein and is regulated by a novel mechanism involving Dam and oxyR.J. Bacteriol. 1999; 181 (10094691): 2132-214110.1128/JB.181.7.2132-2141.1999Crossref PubMed Google Scholar, 31de Luna M. das G. Scott-Tucker A. Desvaux M. Ferguson P. Morin N.P. Dudley E.G. Turner S. Nataro J.P. Owen P. Henderson I.R. The Escherichia coli biofilm-promoting protein Antigen 43 does not contribute to intestinal colonization.FEMS Microbiol. Lett. 2008; 284 (18507683): 237-24610.1111/j.1574-6968.2008.01207.xCrossref PubMed Scopus (13) Google Scholar, 32Wang Y. Andole Pannuri A. Ni D. Zhou H. Cao X. Lu X. Romeo T. Huang Y. Structural basis for translocation of a biofilm-supporting exopolysaccharide across the bacterial outer membrane.J. Biol. Chem. 2016; 291 (26957546): 10046-1005710.1074/jbc.M115.711762Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 33Acheson J.F. Derewenda Z.S. Zimmer J. Architecture of the cellulose synthase outer membrane channel and its association with the periplasmic TPR domain.Structure. 2019; 27 (31604608): 1855-1861.e310.1016/j.str.2019.09.008Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar), and cell defense (34Stumpe S. Schmid R. Stephens D.L. Georgiou G. Bakker E.P. Identification of OmpT as the protease that hydrolyzes the antimicrobial peptide protamine before it enters growing cells of Escherichia coli.J. Bacteriol. 1998; 180 (9683502): 4002-400610.1128/JB.180.15.4002-4006.1998Crossref PubMed Google Scholar, 35Hwang B.-Y. Varadarajan N. Li H. Rodriguez S. Iverson B.L. Georgiou G. Substrate specificity of the Escherichia coli outer membrane protease OmpP.J. Bacteriol. 2007; 189 (17085556): 522-53010.1128/JB.01493-06Crossref PubMed Scopus (25) Google Scholar). Despite the enormous diversity of OMPs in E. coli, it is perhaps surprising that only two are essential: the 16-stranded BamA and 26-stranded LptD (36Ruiz N. Kahne D. Silhavy T.J. Advances in understanding bacterial outer-membrane biogenesis.Nat. Rev. Microbiol. 2006; 4 (16357861): 57-6610.1038/nrmicro1322Crossref PubMed Scopus (320) Google Scholar) (Fig. 1). This is perhaps even more remarkable considering that LptD itself relies on BamA for its assembly (37Lee J. Xue M. Wzorek J.S. Wu T. Grabowicz M. Gronenberg L.S. Sutterlin H.A. Davis R.M. Ruiz N. Silhavy T.J. Kahne D.E. Characterization of a stalled complex on the β-barrel assembly machine.Proc. Natl. Acad. Sci. U. S. A. 2016; 113 (27439868): 8717-872210.1073/pnas.1604100113Crossref PubMed Scopus (49) Google Scholar). LptD's biological role is to insert the lipid component of the outer leaflet of the OM (22Braun M. Silhavy T.J. Imp/OstA is required for cell envelope biogenesis in Escherichia coli.Mol. Microbiol. 2002; 45 (12207697): 1289-130210.1046/j.1365-2958.2002.03091.xCrossref PubMed Scopus (178) Google Scholar, 38Gu Y. Stansfeld P.J. Zeng Y. Dong H. Wang W. Dong C. Lipopolysaccharide is inserted into the outer membrane through an intramembrane hole, a lumen gate, and the lateral opening of LptD.Structure. 2015; 23 (25684578): 496-50410.1016/j.str.2015.01.001Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). BamA (part of the β-barrel assembly machinery, BAM) is required to fold and insert most (but not all) OMPs into the OM in vivo (39Ricci D.P. Silhavy T.J. Outer membrane protein insertion by the β-barrel assembly machine.EcoSal Plus. 2019; 8 (30869065)10.1128/ecosalplus.ESP-0035-2018PubMed Google Scholar) (Table 1). The importance of BAM for the biogenesis of the OM is illustrated by the observation that despite the evolutionary distance between bacteria and eukaryotes, a homologue of BamA, Sam50, is retained in all mitochondria (70Paschen S.A. Neupert W. Rapaport D. Biogenesis of β-barrel membrane proteins of mitochondria.Trends Biochem. Sci. 2005; 30 (16126389): 575-58210.1016/j.tibs.2005.08.009Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Although only BamA and LptD are essential in E. coli under laboratory conditions, it is likely that many more OMPs will be necessary for bacteria to survive, invade new niches, and thrive in diverse environments. Understanding how OMPs fold has been the goal of researchers for approximately the last 3 decades, since the first observations were made that OMPs are capable of folding spontaneously into reconstituted lipid bilayers (71Surrey T. Jähnig F. Refolding and oriented insertion of a membrane protein into a lipid bilayer.Proc. Natl. Acad. Sci. U. S. A. 1992; 89 (1502158): 7457-746110.1073/pnas.89.16.7457Crossref PubMed Google Scholar). Initially, the study of the structure and folding mechanisms of OMPs lagged behind those of their α-helical membrane protein counterparts, because the latter are more abundant in eukaryotes and were considered, initially at least, to be more important from the perspective of human health, as half of all approved drugs target α-helical membrane proteins (72Yildirim M.A. Goh K.-I. Cusick M.E. Barabási A.-L. Vidal M. Drug-target network.Nat. Biotechnol. 2007; 25 (17921997): 1119-112610.1038/nbt1338Crossref PubMed Scopus (1253) Google Scholar, 73Yin H. Flynn A.D. Drugging membrane protein interactions.Annu. Rev. Biomed. Eng. 2016; 18 (26863923): 51-7610.1146/annurev-bioeng-092115-025322Crossref PubMed Scopus (95) Google Scholar). However, in the last 15 years, it has become clear that OMPs are ubiquitous, and some are essential in bacteria (i.e. BamA and LptD) or in mitochondria (i.e. Sam50 and Tom40) (22Braun M. Silhavy T.J. Imp/OstA is required for cell envelope biogenesis in Escherichia coli.Mol. Microbiol. 2002; 45 (12207697): 1289-130210.1046/j.1365-2958.2002.03091.xCrossref PubMed Scopus (178) Google Scholar, 23Voulhoux R. Bos M.P. Geurtsen J. Mols M. Tommassen J. Role of a highly conserved bacterial protein in outer membrane protein assembly.Science. 2003; 299 (12522254): 262-26510.1126/science.1078973Crossref PubMed Scopus (545) Google Scholar, 74Genevrois S. Steeghs L. Roholl P. Letesson J.-J. van der Ley P. The Omp85 protein of Neisseria meningitidis is required for lipid export to the outer membrane.EMBO J. 2003; 22 (12682011): 1780-178910.1093/emboj/cdg174Crossref PubMed Scopus (0) Google Scholar, 75Wiedemann N. Kozjak V. Chacinska A. Schönfisch B. Rospert S. Ryan M.T. Pfanner N. Meisinger C. Machinery for protein sorting and assembly in the mitochondrial outer membrane.Nature. 2003; 424 (12891361): 565-57110.1038/nature01753Crossref PubMed Scopus (273) Google Scholar, 76Paschen S.A. Waizenegger T. Stan T. Preuss M. Cyrklaff M. Hell K. Rapaport D. Neupert W. Evolutionary conservation of biogenesis of β-barrel membrane proteins.Nature. 2003; 426 (14685243): 862-86610.1038/nature02208Crossref PubMed Scopus (322) Google Scholar, 77Kozjak V. Wiedemann N. Milenkovic D. Lohaus C. Meyer H.E. Guiard B. Meisinger C. Pfanner N. An essential role of Sam50 in the protein sorting and assembly machinery of the mitochondrial outer membrane.J. Biol. Chem. 2003; 278 (14570913): 48520-4852310.1074/jbc.C300442200Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). Furthermore, the growth in antibiotic-resistant pathogens has highlighted the importance of the OM as a formidable barrier to the entry of antibiotics into bacteria as well as a site of efflux out (78Nikaido H. Molecular basis of bacterial outer membrane permeability revisited.Microbiol. Mol. Biol. Rev. 2003; 67 (14665678): 593-65610.1128/mmbr.67.4.593-656.2003Crossref PubMed Scopus (2438) Google Scholar) and as a shield against recognition of surface epitopes by natural or designed antibodies (79Domínguez-Medina C.C. Pérez-Toledo M. Schager A.E. Marshall J.L. Cook C.N. Bobat S. Hwang H. Chun B.J. Logan E. Bryant J.A. Channell W.M. Morris F.C. Jossi S.E. Alshayea A. Rossiter A.E. et al.Outer membrane protein size and LPS O-antigen define protective antibody targeting to the Salmonella surface.Nat. Commun. 2020; 11 (32051408): 85110.1038/s41467-020-14655-9Crossref PubMed Scopus (7) Google Scholar, 80Storek K.M. Vij R. Sun D. Smith P.A. Koerber J.T. Rutherford S.T. The Escherichia coli β-barrel assembly machinery is sensitized to perturbations under high membrane fluidity.J. Bacteriol. 2018; 201 (30322857): 1-1510.1128/jb.00517-18Crossref Scopus (6) Google Scholar, 81Bentley A.T. Klebba P.E. Effect of lipopolysaccharide structure on reactivity of antiporin monoclonal antibodies with the bacterial cell surface.J. Bacteriol. 1988; 170 (2830227): 1063-106810.1128/jb.170.3.1063-1068.1988Crossref PubMed Scopus (46) Google Scholar, 82Storek K.M. Chan J. Vij R. Chiang N. Lin Z. Bevers J. Koth C.M. Vernes J.-M. Meng Y.G. Yin J. Wallweber H. Dalmas O. Shriver S. Tam C. Schneider K. et al.Massive antibody discovery used to probe structure-function relationships of the essential outer membrane protein LptD.Elife. 2019; 8 (31237236): e4625810.7554/eLife.46258Crossref PubMed Google Scholar). Hence, insights gained from studies of OMP folding and biogenesis are also vital for our understanding of human physiology (83Ellenrieder L. Mårtensson C.U. Becker T. Biogenesis of mitochondrial outer membrane proteins, problems and diseases.Biol. Chem. 2015; 396 (25980382): 1199-121310.1515/hsz-2015-0170Crossref PubMed Scopus (23) Google Scholar) and will be key in guiding our choice of targets for the generation of new antibiotics and vaccines against Gram-negative bacteria (84Tacconelli E. Carrara E. Savoldi A. Harbarth S. Mendelson M. Monnet D.L. Pulcini C. Kahlmeter G. Kluytmans J. Carmeli Y. Ouellette M. Outterson K. Patel J. Cavaleri M. Cox E.M. et al.Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.Lancet Infect. Dis. 2018; 18 (29276051): 318-32710.1016/S1473-3099(17)30753-3Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar). Consequently, a number of academic groups and drug companies have ongoing research projects targeting the essential OMPs BamA (the central β-barrel-containing subunit of BAM) and LptD (80Storek K.M. Vij R. Sun D. Smith P.A. Koerber J.T. Rutherford S.T. The Escherichia coli β-barrel assembly machinery is sensitized to perturbations under high membrane fluidity.J. Bacteriol. 2018; 201 (30322857): 1-1510.1128/jb.00517-18Crossref Scopus (6) Google Scholar, 82Storek K.M. Chan J. Vij R. Chiang N. Lin Z. Bevers J. Koth C.M. Vernes J.-M. Meng Y.G. Yin J. Wallweber H. Dalmas O. Shriver S. Tam C. Schneider K. et al.Massive antibody discovery used to probe structure-function relationships of the essential outer membrane protein LptD.Elife. 2019; 8 (31237236): e4625810.7554/eLife.46258Crossref PubMed Google Scholar, 85Srinivas N. Jetter P. Ueberbacher B.J. Werneburg M. Zerbe K. Steinmann J. Van der Meijden B. Bernardini F. Lederer A. Dias R.L.A. Misson P.E. Henze H. Zumbrunn J. Gombert F.O. Obrecht D. et al.Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa.Science. 2010; 327 (20167788): 1010-101310.1126/science.1182749Crossref PubMed Scopus (350) Google Scholar, 86Wedege E. Lie K. Bolstad K. Weynants V.E. Halstensen A. Herstad T.K. Kreutzberger J. Nome L. Naess L.M. Aase A. Meningococcal omp85 in detergent-extracted outer membrane vesicle vaccines induces high levels of non-functional antibodies in mice.Scand. J. Immunol. 2013; 77 (23521186): 452-45910.1111/sji.12051Crossref PubMed Scopus (2) Google Scholar, 87Vetterli S.U. Moehle K. Robinson J.A. Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic β-hairpin peptidomimetic antibiotics containing N-methylated amino acids.Bioorg. Med. Chem. 2016; 24 (27240465): 6332-633910.1016/j.bmc.2016.05.027Crossref PubMed Scopus (13) Google Scholar, 88Machutta C.A. Kollmann C.S. Lind K.E. Bai X. Chan P.F. Huang J. Ballell L. Belyanskaya S. Besra G.S. Barros-Aguirre D. Bates R.H. Centrella P.A. Chang S.S. Chai J. Choudhry A.E. et al.Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.Nat. Commun. 2017; 8 (28714473): 1608110.1038/ncomms16081Crossref PubMed Scopus (32) Google Scholar, 89Vij R. Lin Z. Chiang N. Vernes J.-M. Storek K.M. Park S. Chan J. Meng Y.G. Comps-Agrar L. Luan P. Lee S. Schneider K. Bevers J. Zilberleyb I. Tam C. et al.A targeted boost-and-sort immunization strategy using Escherichia coli: BamA identifies rare growth inhibitory antibodies.Sci. Rep. 2018; 8 (29740124): 713610.1038/s41598-018-25609-zCrossref PubMed Scopus (9) Google Scholar, 90Ghequire M.G.K. Swings T. Michiels J. Buchanan S.K. De Mot R. Hitting with a BAM: selective killing by lectin-like bacteriocins.MBio. 2018; 9 (29559575): e02117-e0213810.1128/mBio.02138-17Crossref Scopus (19) Google Scholar, 91Kaur H. Hartmann J.-B. Jakob R.P. Zahn M. Zimmermann I. Maier T. Seeger M.A. Hiller S. Identification of conformation-selective nanobodies against the membrane protein insertase BamA by an integrated structural biology approach.J. Biomol. NMR. 2019; 73 (31073665): 375-38410.1007/s10858-019-00250-8Crossref PubMed Scopus (9) Google Scholar, 92Ghequire M.G.K. De Mot R. LlpB represents a second subclass of lectin-like bacteriocins.Microb. Biotechnol. 2019; 12 (30702207): 567-57310.1111/1751-7915.13373Crossref PubMed Scopus (3) Google Scholar), with at least six reports of inhibitors of their function in 2018-2019 alone (93Storek K.M. Auerbach M.R. Shi H. Garcia N.K. Sun D. Nickerson N.N. Vij R. Lin Z. Chiang N. Schneider K. Wecksler A.T. Skippington E. Nakamura G. Seshasayee D. Koerber J.T. et al.Monoclonal antibody targeting the β-barrel assembly machine of Escherichia coli is bactericidal.Proc. Natl. Acad. Sci. U. S. A. 2018; 115 (29555747): 3692-369710.1073/pnas.1800043115Crossref PubMed Scopus (0) Google Scholar, 94Psonis J.J. Chahales P. Henderson N.S. Rigel N.W. Hoffman P.S. Thanassi D.G. The small molecule nitazoxanide selectively disrupts BAM-mediated folding of the outer membrane usher protein.J. Biol. Chem. 2019; 294 (31391254): 14357-1436910.1074/jbc.RA119.009616Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 95Steenhuis M. Abdallah A.M. de Munnik S.M. Kuhne S. Sterk G.-J. van den Berg van Saparoea B. Westerhausen S. Wagner S. van der Wel N.N. Wijtmans M. van Ulsen P. Jong W.S.P. Luirink J. Inhibition of autotransporter biogenesis by small molecules.Mol. Microbiol. 2019; 112 (30983025): 81-9810.1111/mmi.14255Crossref PubMed Scopus (5) Google Scholar, 96Luther A. Urfer M. Zahn M. Müller M. Wang S. Mondal M. Vitale A. Hartmann J. Sharpe T. Monte F.L. Kocherla H. Cline E. Pessi G. Rath P. Modaresi S.M. et al.Chimeric peptidomimetic antibiotics against Gram-negative bacteria.Nature. 2019; 576 (31645764): 452-45810.1038/s41586-019-1665-6Crossref PubMed Scopus (58) Google Scholar, 97Imai Y. Meyer K.J. Iinishi A. Favre-Godal Q. Green R. Manuse S. Caboni M. Mori M. Niles S. Ghiglieri M. Honrao C. Ma X. Guo J.J. Makriyannis A. Linares-Otoya L. et al.A new antibiotic selectively kills Gram-negative pathogens.Nature. 2019; 576 (31747680): 459-46410.1038/s41586-019-1791-1Crossref PubMed Scopus (86) Google Scholar, 98Hart E.M. Mitchell A.M. Konovalova A. Grabowicz M. Sheng J. Han X. Rodriguez-Rivera F.P. Schwaid A.G. Malinverni J.C. Balibar C.J. Bodea S. Si Q. Wang H. Homsher M.F. Painter R.E. et al.A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier.Proc. Natl. Acad. Sci. U. S. A. 2019; 116 (31591200): 21748-2175710.1073/pnas.1912345116Crossref PubMed Scopus (0) Google Scholar).Table 1Summary of BAM-dependent and BAM-independent OMPs in the OM of different bacteriaOMP(s)FamilyNo. of β-strandsOrganismReferenceBAM catalysis–involved OmpA, OmpX, OmpT, OmPLA, OmpGVaried small barrels8–14E. coliaThese studies were all performed in vitro.Refs. 40Burgess N.K. Dao T.P. Stanley A.M. Fleming K.G. β-Barrel proteins that reside in the Escherichia coli outer membrane in vivo demonstrate varied folding behavior in vitro.J. Biol. Chem. 2008; 283 (18641391): 26748-2675810.1074/jbc.M802754200Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar41Gessmann D. Chung Y.H. Danoff E.J. Plummer A.M. Sandlin C.W. Zaccai N.R. Fleming K.G. Outer membrane β-barrel protein folding is physically controlled by periplasmic lipid head groups and BamA.Proc. Natl. Acad. Sci. U. S. A. 2014; 111 (24715731): 5878-588310.1073/pnas.1322473111Crossref PubMed Scopus (117) Google Scholar, 42Iadanza M.G. Higgins A.J. Schiffrin B. Calabrese A.N. Brockwell D.J. Ashcroft A.E. Radford S.E. Ranson N.A. Lateral opening in the intact β-barrel assembly machinery captured by cryo-EM.Nat. Commun. 2016; 7 (27686148): 1286510.1038/ncomms12865Crossref PubMed Scopus (84) Google Scholar, 43Hagan C.L. Kim S. Kahne D. Reconstitution of outer membrane protein assembly from purified components.Science. 2010; 328 (20378773): 890-89210.1126/science.1188919Crossref PubMed Scopus (183) Google Scholar, 44Hagan C.L. Westwood D.B. Kahne D. Bam lipoprot

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