1887

Microbiology Society logo

Volume 170, Issue 2

Molecular insights into the determinants of substrate specificity and efflux inhibition of the RND efflux pumps AcrB and AdeB Open Access

This article is part of the Antimicrobial Efflux collection.

Abstract

Gram-negative bacterial members of the Resistance Nodulation and cell Division (RND) superfamily form tripartite efflux pump systems that span the cell envelope. One of the intriguing features of the multiple drug efflux members of this superfamily is their ability to recognize different classes of antibiotics, dyes, solvents, bile salts, and detergents. This review provides an overview of the molecular mechanisms of multiple drug efflux catalysed by the tripartite RND efflux system AcrAB-TolC from . The determinants for sequential or simultaneous multiple substrate binding and efflux pump inhibitor binding are discussed. A comparison is made with the determinants for substrate binding of AdeB from , which acts within the AdeABC multidrug efflux system. There is an apparent general similarity between the structures of AcrB and AdeB and their substrate specificity. However, the presence of distinct conformational states and different drug efflux capacities as revealed by single-particle cryo-EM and mutational analysis suggest that the drug binding and transport features exhibited by AcrB may not be directly extrapolated to the homolog AdeB efflux pump.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antibiotic resistance , efflux , efflux pump inhibitors , polyspecificity , Resistance Nodulation cell Division (RND) and tripartite systems
Funding
This study was supported by the:
  • Deutsche Forschungsgemeinschaft (Award SFB807-P18)
    • Principle Award Recipient: KlaasMartinus Pos
  • Bundesministerium für Bildung und Forschung (Award 16GW0236K)
    • Principle Award Recipient: KlaasMartinus Pos
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. The Microbiology Society waived the open access fees for this article.
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.001438
2024-02-15
2024-05-08
Loading full text...

Full text loading...

/deliver/fulltext/micro/170/2/mic001438.html?itemId=/content/journal/micro/10.1099/mic.0.001438&mimeType=html&fmt=ahah

References

  1. WHO Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics; 20171–7
  2. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018; 18:318–327 [View Article] [PubMed]
     [Google Scholar]
  3. Murray CJL, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 2022; 399:629–655 [View Article]
     [Google Scholar]
  4. Darby EM, Trampari E, Siasat P, Gaya MS, Alav I et al. Molecular mechanisms of antibiotic resistance revisited. Nat Rev Microbiol 2023; 21:280–295 [View Article] [PubMed]
     [Google Scholar]
  5. Alav I, Sutton JM, Rahman KM. Role of bacterial efflux pumps in biofilm formation. J Antimicrob Chemother 2018; 73:2003–2020 [View Article] [PubMed]
     [Google Scholar]
  6. Wang-Kan X, Blair JMA, Chirullo B, Betts J, La Ragione RM et al. Lack of AcrB efflux function confers loss of virulence on Salmonella enterica serovar typhimurium. mBio 2017; 8:e00968-17 [View Article] [PubMed]
     [Google Scholar]
  7. Nikaido H. Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 2003; 67:593–656 [View Article] [PubMed]
     [Google Scholar]
  8. Nikaido H, Pagès JM. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol Rev 2012; 36:340–363 [View Article] [PubMed]
     [Google Scholar]
  9. Yoshimura F, Nikaido H. Diffusion of beta-lactam antibiotics through the porin channels of Escherichia coli K-12. Antimicrob Agents Chemother 1985; 27:84–92 [View Article]
     [Google Scholar]
  10. Vergalli J, Bodrenko IV, Masi M, Moynié L, Acosta-Gutiérrez S et al. Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria. Nat Rev Microbiol 2020; 18:164–176 [View Article] [PubMed]
     [Google Scholar]
  11. Pagès JM, James CE, Winterhalter M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 2008; 6:893–903 [View Article] [PubMed]
     [Google Scholar]
  12. Sugawara E, Nikaido H. OmpA is the principal nonspecific slow porin of Acinetobacter baumannii. J Bacteriol 2012; 194:4089–4096 [View Article] [PubMed]
     [Google Scholar]
  13. Nikaido H. Multidrug efflux pumps of gram-negative bacteria. J Bacteriol 1996; 178:5853–5859 [View Article] [PubMed]
     [Google Scholar]
  14. Shuster Y, Steiner-Mordoch S, Alon Cudkowicz N, Schuldiner S. A transporter interactome is essential for the acquisition of antimicrobial resistance to antibiotics. PLoS One 2016; 11:e0152917 [View Article] [PubMed]
     [Google Scholar]
  15. Rahman T, Yarnall B, Doyle DA. Efflux drug transporters at the forefront of antimicrobial resistance. Eur Biophys J 2017; 46:647–653 [View Article] [PubMed]
     [Google Scholar]
  16. Tal N, Schuldiner S. A coordinated network of transporters with overlapping specificities provides a robust survival strategy. Proc Natl Acad Sci U S A 2009; 106:9051–9056 [View Article] [PubMed]
     [Google Scholar]
  17. Sulavik MC, Houseweart C, Cramer C, Jiwani N, Murgolo N et al. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob Agents Chemother 2001; 45:1126–1136 [View Article] [PubMed]
     [Google Scholar]
  18. Nishino K, Yamaguchi A. Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 2001; 183:5803–5812 [View Article] [PubMed]
     [Google Scholar]
  19. de Cristóbal RE, Vincent PA, Salomón RA. Multidrug resistance pump AcrAB-TolC is required for high-level, Tet(A)-mediated tetracycline resistance in Escherichia coli. J Antimicrob Chemother 2006; 58:31–36 [View Article] [PubMed]
     [Google Scholar]
  20. Teelucksingh T, Thompson LK, Zhu S, Kuehfuss NM, Goetz JA et al. A genetic platform to investigate the functions of bacterial drug efflux pumps. Nat Chem Biol 2022; 18:1399–1409 [View Article] [PubMed]
     [Google Scholar]
  21. Marchand I, Damier-Piolle L, Courvalin P, Lambert T. Expression of the RND-type efflux pump AdeABC in Acinetobacter baumannii is regulated by the AdeRS two-component system. Antimicrob Agents Chemother 2004; 48:3298–3304 [View Article] [PubMed]
     [Google Scholar]
  22. Coyne S, Rosenfeld N, Lambert T, Courvalin P, Périchon B. Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 2010; 54:4389–4393 [View Article] [PubMed]
     [Google Scholar]
  23. Cohen SP, Hächler H, Levy SB. Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli. J Bacteriol 1993; 175:1484–1492 [View Article]
     [Google Scholar]
  24. Webber MA, Talukder A, Piddock LJV. Contribution of mutation at amino acid 45 of AcrR to acrB expression and ciprofloxacin resistance in clinical and veterinary Escherichia coli isolates. Antimicrob Agents Chemother 2005; 49:4390–4392 [View Article] [PubMed]
     [Google Scholar]
  25. Weston N, Sharma P, Ricci V, Piddock LJV. Regulation of the AcrAB-TolC efflux pump in Enterobacteriaceae. Res Microbiol 2018; 169:425–431 [View Article] [PubMed]
     [Google Scholar]
  26. Du D, Wang-Kan X, Neuberger A, van Veen HW, Pos KM et al. Multidrug efflux pumps: structure, function and regulation. Nat Rev Microbiol 2018; 16:523–539 [View Article]
     [Google Scholar]
  27. Blair JMA, Bavro VN, Ricci V, Modi N, Cacciotto P et al. AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. Proc Natl Acad Sci U S A 2015; 112:3511–3516 [View Article] [PubMed]
     [Google Scholar]
  28. Elkins C, Nikaido H. Substrate Speci city of the RND-type multidrug EF ux pumps AcrB and AcrD of. J Bacteriol 2002; 184:6490–6498 [View Article] [PubMed]
     [Google Scholar]
  29. Tikhonova EB, Wang Q, Zgurskaya HI. Chimeric analysis of the multicomponent multidrug efflux transporters from gram-negative bacteria. J Bacteriol 2002; 184:6499–6507 [View Article] [PubMed]
     [Google Scholar]
  30. Eda S, Maseda H, Nakae T. An elegant means of self-protection in gram-negative bacteria by recognizing and extruding xenobiotics from the periplasmic space. J Biol Chem 2003; 278:2085–2088 [View Article] [PubMed]
     [Google Scholar]
  31. Nikaido H. Multidrug resistance in bacteria. Annu Rev Biochem 2009; 78:119–146 [View Article] [PubMed]
     [Google Scholar]
  32. Guan L, Nakae T. Identification of essential charged residues in transmembrane segments of the multidrug transporter MexB of Pseudomonas aeruginosa. J Bacteriol 2001; 183:1734–1739 [View Article] [PubMed]
     [Google Scholar]
  33. Seeger MA, von Ballmoos C, Verrey F, Pos KM. Crucial role of Asp408 in the proton translocation pathway of multidrug transporter AcrB: evidence from site-directed mutagenesis and carbodiimide labeling. Biochemistry 2009; 48:5801–5812 [View Article] [PubMed]
     [Google Scholar]
  34. Su C-C, Li M, Gu R, Takatsuka Y, McDermott G et al. Conformation of the AcrB multidrug efflux pump in mutants of the putative proton relay pathway. J Bacteriol 2006; 188:7290–7296 [View Article] [PubMed]
     [Google Scholar]
  35. Alav I, Bavro VN, Blair JMA. A role for the periplasmic adaptor protein AcrA in vetting substrate access to the RND efflux transporter AcrB. Sci Rep 2022; 12:4752 [View Article] [PubMed]
     [Google Scholar]
  36. Daury L, Orange F, Taveau J-C, Verchère A, Monlezun L et al. Tripartite assembly of RND multidrug efflux pumps. Nat Commun 2016; 7:10731 [View Article] [PubMed]
     [Google Scholar]
  37. Wang Z, Fan G, Hryc CF, Blaza JN, Serysheva II et al. An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump. Elife 2017; 6:1–19 [View Article] [PubMed]
     [Google Scholar]
  38. Tsutsumi K, Yonehara R, Ishizaka-Ikeda E, Miyazaki N, Maeda S et al. Structures of the wild-type MexAB-OprM tripartite pump reveal its complex formation and drug efflux mechanism. Nat Commun 2019; 10:1520 [View Article] [PubMed]
     [Google Scholar]
  39. Glavier M, Puvanendran D, Salvador D, Decossas M, Phan G et al. Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex. Nat Commun 2020; 11:4948 [View Article] [PubMed]
     [Google Scholar]
  40. Du D, Wang Z, James NR, Voss JE, Klimont E et al. Structure of the AcrAB-TolC multidrug efflux pump. Nature 2014; 509:512–515 [View Article] [PubMed]
     [Google Scholar]
  41. Hobbs EC, Yin X, Paul BJ, Astarita JL, Storz G. Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance. Proc Natl Acad Sci U S A 2012; 109:16696–16701 [View Article] [PubMed]
     [Google Scholar]
  42. Alav I, Kobylka J, Kuth MS, Pos KM, Picard M et al. Structure, assembly, and function of tripartite efflux and type 1 secretion systems in Gram-negative bacteria. Chem Rev 2021; 121:5479–5596 [View Article] [PubMed]
     [Google Scholar]
  43. Zgurskaya HI, Walker JK, Parks JM, Rybenkov VV. Multidrug efflux pumps and the two-faced janus of substrates and inhibitors. Acc Chem Res 2021; 54:930–939 [View Article] [PubMed]
     [Google Scholar]
  44. Krishnamoorthy G, Leus IV, Weeks JW, Wolloscheck D, Rybenkov VV et al. Synergy between active efflux and outer membrane diffusion defines rules of antibiotic permeation into Gram-negative bacteria. mBio 2017; 8:e01172-17 [View Article] [PubMed]
     [Google Scholar]
  45. Saier MH, Tran CV, Barabote RD. TCDB: the transporter classification database for membrane transport protein analyses and information. Nucleic Acids Res 2006; 34:D181–6 [View Article] [PubMed]
     [Google Scholar]
  46. Saier MH, Reddy VS, Tsu BV, Ahmed MS, Li C et al. The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res 2016; 44:D372–9 [View Article] [PubMed]
     [Google Scholar]
  47. Saier MH, Reddy VS, Moreno-Hagelsieb G, Hendargo KJ, Zhang Y et al. The Transporter Classification Database (TCDB): 2021 update. Nucleic Acids Res 2021; 49:D461–D467 [View Article] [PubMed]
     [Google Scholar]
  48. Thomas C, Tampé R. Structural and mechanistic principles of ABC transporters. Annu Rev Biochem 2020; 89:605–636 [View Article] [PubMed]
     [Google Scholar]
  49. Kornelsen V, Kumar A. Update on multidrug resistance efflux pumps in Acinetobacter spp. Antimicrob Agents Chemother 2021; 65:e0051421 [View Article] [PubMed]
     [Google Scholar]
  50. Kim J, Cater RJ, Choy BC, Mancia F. Structural Insights into transporter-mediated drug resistance in infectious diseases. J Mol Biol 2021; 433:167005 [View Article] [PubMed]
     [Google Scholar]
  51. Henderson PJF, Maher C, Elbourne LDH, Eijkelkamp BA, Paulsen IT et al. Physiological functions of bacterial “Multidrug” efflux pumps. Chem Rev 2021; 121:5417–5478 [View Article] [PubMed]
     [Google Scholar]
  52. Tseng TT, Gratwick KS, Kollman J, Park D, Nies DH et al. The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J Mol Microbiol Biotechnol 1999; 1:107–125 [PubMed]
     [Google Scholar]
  53. Nikaido H. RND transporters in the living world. Res Microbiol 2018; 169:363–371 [View Article] [PubMed]
     [Google Scholar]
  54. Tsukazaki T. Structure-based working model of SecDF, a proton-driven bacterial protein translocation factor. FEMS Microbiol Lett 2018; 365:fny112 [View Article] [PubMed]
     [Google Scholar]
  55. Pogliano JA, Beckwith J. SecD and SecF facilitate protein export in Escherichia coli. EMBO J 1994; 13:554–561 [View Article] [PubMed]
     [Google Scholar]
  56. Varela C, Rittmann D, Singh A, Krumbach K, Bhatt K et al. MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol 2012; 19:498–506 [View Article] [PubMed]
     [Google Scholar]
  57. Adams O, Deme JC, Parker JL, Fowler PW, Lea SM et al. Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: an emergent therapeutic target. Structure 2021; 29:1182–1191 [View Article] [PubMed]
     [Google Scholar]
  58. Kumar N, Su C-C, Chou T-H, Radhakrishnan A, Delmar JA et al. Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN. Proc Natl Acad Sci U S A 2017; 114:6557–6562 [View Article] [PubMed]
     [Google Scholar]
  59. Maher C, Hassan KA. The Gram-negative permeability barrier: tipping the balance of the in and the out. mBio 2023; 14:e0120523 [View Article] [PubMed]
     [Google Scholar]
  60. Kobylka J, Kuth MS, Müller RT, Geertsma ER, Pos KM. AcrB: a mean, keen, drug efflux machine. Ann N Y Acad Sci 2020; 1459:38–68 [View Article] [PubMed]
     [Google Scholar]
  61. Klenotic PA, Moseng MA, Morgan CE, Yu EW. Structural and functional diversity of resistance-nodulation-cell division transporters. Chem Rev 2021; 121:5378–5416 [View Article] [PubMed]
     [Google Scholar]
  62. Murakami S, Nakashima R, Yamashita E, Yamaguchi A. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 2002; 419:587–593 [View Article] [PubMed]
     [Google Scholar]
  63. Eicher T, Seeger MA, Anselmi C, Zhou W, Brandstätter L et al. Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB. Elife 2014; 3:1–26 [View Article] [PubMed]
     [Google Scholar]
  64. Takatsuka Y, Nikaido H. Threonine-978 in the transmembrane segment of the multidrug efflux pump AcrB of Escherichia coli is crucial for drug transport as a probable component of the proton relay network. J Bacteriol 2006; 188:7284–7289 [View Article] [PubMed]
     [Google Scholar]
  65. Kim J-S, Jeong H, Song S, Kim H-Y, Lee K et al. Structure of the tripartite multidrug efflux pump AcrAB-TolC suggests an alternative assembly mode. Mol Cells 2015; 38:180–186 [View Article] [PubMed]
     [Google Scholar]
  66. Jeong H, Kim J-S, Song S, Shigematsu H, Yokoyama T et al. Pseudoatomic structure of the tripartite multidrug efflux pump AcrAB-TolC reveals the intermeshing cogwheel-like interaction between AcrA and TolC. Structure 2016; 24:272–276 [View Article] [PubMed]
     [Google Scholar]
  67. Tsutsumi K, Yonehara R, Ishizaka-Ikeda E, Miyazaki N, Maeda S et al. Structures of the wild-type MexAB-OprM tripartite pump reveal its complex formation and drug efflux mechanism. Nat Commun 2019; 10:1520 [View Article] [PubMed]
     [Google Scholar]
  68. Glavier M, Puvanendran D, Salvador D, Decossas M, Phan G et al. Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex. Nat Commun 2020; 11:4948 [View Article] [PubMed]
     [Google Scholar]
  69. Takatsuka Y, Nikaido H. Site-directed disulfide cross-linking shows that cleft flexibility in the periplasmic domain is needed for the multidrug efflux pump AcrB of Escherichia coli. J Bacteriol 2007; 189:8677–8684 [View Article] [PubMed]
     [Google Scholar]
  70. Rahman MM, Matsuo T, Ogawa W, Koterasawa M, Kuroda T et al. Molecular cloning and characterization of all RND-type efflux transporters in Vibrio cholerae non-O1. Microbiol Immunol 2007; 51:1061–1070 [View Article] [PubMed]
     [Google Scholar]
  71. Kim HS, Nagore D, Nikaido H. Multidrug efflux pump MdtBC of Escherichia coli is active only as a B2C heterotrimer. J Bacteriol 2010; 192:1377–1386 [View Article] [PubMed]
     [Google Scholar]
  72. Kim H-S, Nikaido H. Different functions of MdtB and MdtC subunits in the heterotrimeric efflux transporter MdtB(2)C complex of Escherichia coli. Biochemistry 2012; 51:4188–4197 [View Article] [PubMed]
     [Google Scholar]
  73. Sennhauser G, Bukowska MA, Briand C, Grütter MG. Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. J Mol Biol 2009; 389:134–145 [View Article] [PubMed]
     [Google Scholar]
  74. Bolla JR, Su C-C, Do SV, Radhakrishnan A, Kumar N et al. Crystal structure of the Neisseria gonorrhoeae MtrD inner membrane multidrug efflux pump. PLoS ONE 2014; 9:e97903 [View Article] [PubMed]
     [Google Scholar]
  75. Su C-C, Yin L, Kumar N, Dai L, Radhakrishnan A et al. Structures and transport dynamics of a Campylobacter jejuni multidrug efflux pump. Nat Commun 2017; 8:171 [View Article] [PubMed]
     [Google Scholar]
  76. Su C-C, Morgan CE, Kambakam S, Rajavel M, Scott H et al. Cryo-electron microscopy structure of an Acinetobacter baumannii multidrug efflux pump. mBio 2019; 10:1–13 [View Article] [PubMed]
     [Google Scholar]
  77. Morgan CE, Glaza P, Leus IV, Trinh A, Su C-C et al. Cryoelectron microscopy structures of AdeB illuminate mechanisms of simultaneous binding and exporting of substrates. mBio 2021; 12:1–15 [View Article] [PubMed]
     [Google Scholar]
  78. Ornik-Cha A, Wilhelm J, Kobylka J, Sjuts H, Vargiu AV et al. Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms. Nat Commun 2021; 12:6919 [View Article] [PubMed]
     [Google Scholar]
  79. Johnson RM, Fais C, Parmar M, Cheruvara H, Marshall RL et al. Cryo-EM structure and molecular dynamics analysis of the fluoroquinolone resistant mutant of the AcrB transporter from Salmonella. Microorganisms 2020; 8:1–21 [View Article] [PubMed]
     [Google Scholar]
  80. Fabre L, Ntreh AT, Yazidi A, Leus IV, Weeks JW et al. A “Drug Sweeping” state of the TriABC triclosan efflux pump from Pseudomonas aeruginosa. Structure 2021; 29:261–274 [View Article] [PubMed]
     [Google Scholar]
  81. Lyu M, Moseng MA, Reimche JL, Holley CL, Dhulipala V et al. Cryo-EM structures of a gonococcal multidrug efflux pump illuminate a mechanism of drug recognition and resistance. mBio 2020; 11:1–15 [View Article] [PubMed]
     [Google Scholar]
  82. Zhang Z, Morgan CE, Bonomo RA, Yu EW. Cryo-EM determination of Eravacycline-bound structures of the Baumannii. mBio 2021; 12:e01031–21 [View Article]
     [Google Scholar]
  83. Zhang Z, Morgan CE, Cui M, Yu EW, Engelman AN. Cryo-EM structures of AcrD illuminate a mechanism for capturing Aminoglycosides from its central cavity. mBio 2023; 14:e0338322 [View Article] [PubMed]
     [Google Scholar]
  84. Bharatham N, Bhowmik P, Aoki M, Okada U, Sharma S et al. Structure and function relationship of OqxB efflux pump from Klebsiella pneumoniae. Nat Commun 2021; 12:5400 [View Article] [PubMed]
     [Google Scholar]
  85. Kato T, Okada U, Hung L-W, Yamashita E, Kim H-B et al. Crystal structures of multidrug efflux transporters from Burkholderia pseudomallei suggest details of transport mechanism. Proc Natl Acad Sci U S A 2023; 120:e2215072120 [View Article] [PubMed]
     [Google Scholar]
  86. Deininger KNW, Horikawa A, Kitko RD, Tatsumi R, Rosner JL et al. A requirement of TolC and MDR efflux pumps for acid adaptation and GadAB induction in Escherichia coli. PLoS One 2011; 6:e18960 [View Article] [PubMed]
     [Google Scholar]
  87. Schaffner SH, Lee AV, Pham MTN, Kassaye BB, Li H et al. Extreme acid modulates fitness trade-offs of multidrug efflux pumps MdtEF-TolC and AcrAB-TolC in Escherichia coli K-12. Appl Environ Microbiol 2021; 87:e0072421 [View Article] [PubMed]
     [Google Scholar]
  88. Zhang Y, Xiao M, Horiyama T, Zhang Y, Li X et al. The multidrug efflux pump MdtEF protects against nitrosative damage during the anaerobic respiration in Escherichia coli. J Biol Chem 2011; 286:26576–26584 [View Article] [PubMed]
     [Google Scholar]
  89. Rosenberg EY, Ma D, Nikaido H. AcrD of Escherichia coli is an aminoglycoside efflux pump. J Bacteriol 2000; 182:1754–1756 [View Article] [PubMed]
     [Google Scholar]
  90. Ramaswamy VK, Vargiu AV, Malloci G, Dreier J, Ruggerone P. Molecular rationale behind the differential substrate specificity of bacterial RND multi-drug transporters. Sci Rep 2017; 7:8075 [View Article] [PubMed]
     [Google Scholar]
  91. Cuesta Bernal J, El-Delik J, Göttig S, Pos KM. Characterization and molecular determinants for β-lactam specificity of the multidrug efflux pump AcrD from Salmonella typhimurium. Antibiotics (Basel) 2021; 10:1494 [View Article] [PubMed]
     [Google Scholar]
  92. Nikaido H, Basina M, Nguyen V, Rosenberg EY. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those beta-lactam antibiotics containing lipophilic side chains. J Bacteriol 1998; 180:4686–4692 [View Article] [PubMed]
     [Google Scholar]
  93. Zgurskaya HI, López CA, Gnanakaran S. Permeability barrier of Gram-negative cell envelopes and approaches to bypass it. ACS Infect Dis 2015; 1:512–522 [View Article] [PubMed]
     [Google Scholar]
  94. Lee A, Mao W, Warren MS, Mistry A, Hoshino K et al. Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol 2000; 182:3142–3150 [View Article] [PubMed]
     [Google Scholar]
  95. Foong WE, Wilhelm J, Tam H-K, Pos KM. Tigecycline efflux in Acinetobacter baumannii is mediated by TetA in synergy with RND-type efflux transporters. J Antimicrob Chemother 2020; 75:1135–1139 [View Article] [PubMed]
     [Google Scholar]
  96. Pos KM. Drug transport mechanism of the AcrB efflux pump. Biochim Biophys Acta 2009; 1794:782–793 [View Article] [PubMed]
     [Google Scholar]
  97. Brandstätter L, Sokolova L, Eicher T, Seeger MA, Briand C et al. Analysis of AcrB and AcrB/DARPin ligand complexes by LILBID MS. Biochim Biophys Acta 2011; 1808:2189–2196 [View Article] [PubMed]
     [Google Scholar]
  98. Yu L, Lu W, Wei Y, Sandler SJ. AcrB trimer stability and efflux activity, insight from mutagenesis studies. PLoS ONE 2011; 6:e28390 [View Article] [PubMed]
     [Google Scholar]
  99. Seeger MA, von Ballmoos C, Eicher T, Brandstätter L, Verrey F et al. Engineered disulfide bonds support the functional rotation mechanism of multidrug efflux pump AcrB. Nat Struct Mol Biol 2008; 15:199–205 [View Article] [PubMed]
     [Google Scholar]
  100. Murakami S, Tamura N, Saito A, Hirata T, Yamaguchi A. Extramembrane central pore of multidrug exporter AcrB in Escherichia coli plays an important role in drug transport. J Biol Chem 2004; 279:3743–3748 [View Article] [PubMed]
     [Google Scholar]
  101. Qiu W, Fu Z, Xu GG, Grassucci RA, Zhang Y et al. Structure and activity of lipid bilayer within a membrane-protein transporter. Proc Natl Acad Sci U S A 2018; 115:12985–12990 [View Article] [PubMed]
     [Google Scholar]
  102. Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 2006; 443:173–179 [View Article]
     [Google Scholar]
  103. Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K et al. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 2006; 313:1295–1298 [View Article] [PubMed]
     [Google Scholar]
  104. Sennhauser G, Amstutz P, Briand C, Storchenegger O, Grütter MG. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol 2007; 5:e7 [View Article] [PubMed]
     [Google Scholar]
  105. Nakashima R, Sakurai K, Yamasaki S, Nishino K, Yamaguchi A. Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature 2011; 480:565–569 [View Article]
     [Google Scholar]
  106. Eicher T, Cha H, Seeger MA, Brandstätter L, El-Delik J et al. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. Proc Natl Acad Sci U S A 2012; 109:5687–5692 [View Article] [PubMed]
     [Google Scholar]
  107. Boyer PD. The ATP synthase--a splendid molecular machine. Annu Rev Biochem 1997; 66:717–749 [View Article] [PubMed]
     [Google Scholar]
  108. Takatsuka Y, Nikaido H. Covalently linked trimer of the AcrB multidrug efflux pump provides support for the functional rotating mechanism. J Bacteriol 2009; 191:1729–1737 [View Article] [PubMed]
     [Google Scholar]
  109. Nagano K, Nikaido H. Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci U S A 2009; 106:5854–5858 [View Article] [PubMed]
     [Google Scholar]
  110. Lim SP, Nikaido H. Kinetic parameters of efflux of penicillins by the multidrug efflux transporter AcrAB-TolC of Escherichia coli. Antimicrob Agents Chemother 2010; 54:1800–1806 [View Article] [PubMed]
     [Google Scholar]
  111. Müller RT, Pos KM. The assembly and disassembly of the AcrAB-TolC three-component multidrug efflux pump. Biol Chem 2015; 396:1083–1089 [View Article] [PubMed]
     [Google Scholar]
  112. Yao X-Q, Kenzaki H, Murakami S, Takada S. Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations. Nat Commun 2010; 1:117 [View Article] [PubMed]
     [Google Scholar]
  113. Zwama M, Yamasaki S, Nakashima R, Sakurai K, Nishino K et al. Multiple entry pathways within the efflux transporter AcrB contribute to multidrug recognition. Nat Commun 2018; 9:124 [View Article] [PubMed]
     [Google Scholar]
  114. Oswald C, Tam HK, Pos KM. Transport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB. Nat Commun 2016; 7:13819 [View Article] [PubMed]
     [Google Scholar]
  115. Tam H-K, Malviya VN, Foong W-E, Herrmann A, Malloci G et al. Binding and transport of carboxylated drugs by the multidrug transporter AcrB. J Mol Biol 2020; 432:861–877 [View Article] [PubMed]
     [Google Scholar]
  116. Tam H-K, Foong WE, Oswald C, Herrmann A, Zeng H et al. Allosteric drug transport mechanism of multidrug transporter AcrB. Nat Commun 2021; 12:1–10 [View Article]
     [Google Scholar]
  117. Zgurskaya HI, Nikaido H. Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli. Proc Natl Acad Sci U S A 1999; 96:7190–7195 [View Article] [PubMed]
     [Google Scholar]
  118. Zwama M, Hayashi K, Sakurai K, Nakashima R, Kitagawa K et al. Hoisting-loop in bacterial multidrug exporter AcrB is a highly flexible hinge that enables the large motion of the subdomains. Front Microbiol 2017; 8:2095 [View Article] [PubMed]
     [Google Scholar]
  119. Yamane T, Murakami S, Ikeguchi M. Functional rotation induced by alternating protonation states in the multidrug transporter AcrB: all-atom molecular dynamics simulations. Biochemistry 2013; 52:7648–7658 [View Article] [PubMed]
     [Google Scholar]
  120. Yue Z, Chen W, Zgurskaya HI, Shen J. Constant pH molecular dynamics reveals how proton release drives the conformational transition of a transmembrane efflux pump. J Chem Theory Comput 2017; 13:6405–6414 [View Article] [PubMed]
     [Google Scholar]
  121. Seeger MA, Diederichs K, Eicher T, Brandstätter L, Schiefner A et al. The AcrB efflux pump: conformational cycling and peristalsis lead to multidrug resistance. Curr Drug Targets 2008; 9:729–749 [View Article] [PubMed]
     [Google Scholar]
  122. Yamaguchi A, Nakashima R, Sakurai K. Structural basis of RND-type multidrug exporters. Front Microbiol 2015; 6:327 [View Article] [PubMed]
     [Google Scholar]
  123. Nishino K, Yamada J, Hirakawa H, Hirata T, Yamaguchi A. Roles of TolC-dependent multidrug transporters of Escherichia coli in resistance to beta-lactams. Antimicrob Agents Chemother 2003; 47:3030–3033 [View Article] [PubMed]
     [Google Scholar]
  124. Aires JR, Köhler T, Nikaido H, Plésiat P. Involvement of an active efflux system in the natural resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob Agents Chemother 1999; 43:2624–2628 [View Article] [PubMed]
     [Google Scholar]
  125. Masuda N, Sakagawa E, Ohya S, Gotoh N, Tsujimoto H et al. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-oprM efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2000; 44:3322–3327 [View Article] [PubMed]
     [Google Scholar]
  126. Magnet S, Courvalin P, Lambert T. Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrob Agents Chemother 2001; 45:3375–3380 [View Article] [PubMed]
     [Google Scholar]
  127. Rajamohan G, Srinivasan VB, Gebreyes WA. Novel role of Acinetobacter baumannii RND efflux transporters in mediating decreased susceptibility to biocides. J Antimicrob Chemother 2010; 65:228–232 [View Article] [PubMed]
     [Google Scholar]
  128. Coyne S, Courvalin P, Périchon B. Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob Agents Chemother 2011; 55:947–953 [View Article] [PubMed]
     [Google Scholar]
  129. Sugawara E, Nikaido H. Properties of AdeABC and AdeIJK efflux systems of Acinetobacter baumannii compared with those of the AcrAB-TolC system of Escherichia coli. Antimicrob Agents Chemother 2014; 58:7250–7257 [View Article] [PubMed]
     [Google Scholar]
  130. Yoon E-J, Chabane YN, Goussard S, Snesrud E, Courvalin P et al. Contribution of resistance-nodulation-cell division efflux systems to antibiotic resistance and biofilm formation in Acinetobacter baumannii. mBio 2015; 6:e00309-15 [View Article] [PubMed]
     [Google Scholar]
  131. Richmond GE, Evans LP, Anderson MJ, Wand ME, Bonney LC et al. The Acinetobacter baumannii two-component system AdeRS regulates genes required for multidrug efflux, biofilm formation, and virulence in a strain-specific manner. mBio 2016; 7:e00430-16 [View Article] [PubMed]
     [Google Scholar]
  132. Yu EW, McDermott G, Zgurskaya HI, Nikaido H, Koshland DE. Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 2003; 300:976–980 [View Article] [PubMed]
     [Google Scholar]
  133. Yu EW, Aires JR, McDermott G, Nikaido H. A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study. J Bacteriol 2005; 187:6804–6815 [View Article] [PubMed]
     [Google Scholar]
  134. Törnroth-Horsefield S, Gourdon P, Horsefield R, Brive L, Yamamoto N et al. Crystal structure of AcrB in complex with a single transmembrane subunit reveals another twist. Structure 2007; 15:1663–1673 [View Article] [PubMed]
     [Google Scholar]
  135. Drew D, Klepsch MM, Newstead S, Flaig R, De Gier J-W et al. The structure of the efflux pump AcrB in complex with bile acid. Mol Membr Biol 2008; 25:677–682 [View Article] [PubMed]
     [Google Scholar]
  136. Neyfakh AA. Mystery of multidrug transporters: the answer can be simple. Mol Microbiol 2002; 44:1123–1130 [View Article] [PubMed]
     [Google Scholar]
  137. Zwama M, Yamaguchi A. Molecular mechanisms of AcrB-mediated multidrug export. Res Microbiol 2018; 169:372–383 [View Article] [PubMed]
     [Google Scholar]
  138. Vargiu AV, Ramaswamy VK, Malloci G, Malvacio I, Atzori A et al. Computer simulations of the activity of RND efflux pumps. Res Microbiol 2018; 169:384–392 [View Article] [PubMed]
     [Google Scholar]
  139. Takatsuka Y, Chen C, Nikaido H. Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci U S A 2010; 107:6559–6565 [View Article] [PubMed]
     [Google Scholar]
  140. Vargiu AV, Nikaido H. Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Natl Acad Sci U S A 2012; 109:20637–20642 [View Article] [PubMed]
     [Google Scholar]
  141. Sjuts H, Vargiu AV, Kwasny SM, Nguyen ST, Kim H-S et al. Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proc Natl Acad Sci U S A 2016; 113:3509–3514 [View Article] [PubMed]
     [Google Scholar]
  142. Pos KM. RND multidrug efflux transporters: similar appearances, diverse actions. J Bacteriol 2024; 206:e0040323 [View Article] [PubMed]
     [Google Scholar]
  143. Ababou A, Koronakis V. Structures of gate loop variants of the AcrB drug efflux pump bound by erythromycin substrate. PLoS ONE 2016; 11:e0159154 [View Article] [PubMed]
     [Google Scholar]
  144. Cha H, Müller RT, Pos KM. Switch-loop flexibility affects transport of large drugs by the promiscuous AcrB multidrug efflux transporter. Antimicrob Agents Chemother 2014; 58:4767–4772 [View Article] [PubMed]
     [Google Scholar]
  145. Müller RT, Travers T, Cha H-J, Phillips JL, Gnanakaran S et al. Switch loop flexibility affects substrate transport of the AcrB efflux pump. J Mol Biol 2017; 429:3863–3874 [View Article] [PubMed]
     [Google Scholar]
  146. Ababou A. New insights into the structural and functional involvement of the gate loop in AcrB export activity. Biochim Biophys Acta Proteins Proteom 2018; 1866:242–253 [View Article] [PubMed]
     [Google Scholar]
  147. Long F, Su C-C, Zimmermann MT, Boyken SE, Rajashankar KR et al. Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport. Nature 2010; 467:484–488 [View Article]
     [Google Scholar]
  148. Su C-C, Long F, Lei H-T, Bolla JR, Do SV et al. Charged amino acids (R83, E567, D617, E625, R669, and K678) of CusA are required for metal ion transport in the Cus efflux system. J Mol Biol 2012; 422:429–441 [View Article] [PubMed]
     [Google Scholar]
  149. Leus IV, Roberts SR, Trinh A, W Yu E, Zgurskaya HI. Nonadditive functional interactions between ligand-binding sites of the multidrug efflux pump AdeB from Acinetobacter baumannii. J Bacteriol 2024; 206:e0021723 [View Article] [PubMed]
     [Google Scholar]
  150. Nakashima R, Sakurai K, Yamasaki S, Hayashi K, Nagata C et al. Structural basis for the inhibition of bacterial multidrug exporters. Nature 2013; 500:102–106 [View Article]
     [Google Scholar]
  151. Vargiu AV, Ruggerone P, Opperman TJ, Nguyen ST, Nikaido H. Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob Agents Chemother 2014; 58:6224–6234 [View Article] [PubMed]
     [Google Scholar]
  152. Bohnert JA, Schuster S, Seeger MA, Fähnrich E, Pos KM et al. Site-directed mutagenesis reveals putative substrate binding residues in the Escherichia coli RND efflux pump AcrB. J Bacteriol 2008; 190:8225–8229 [View Article] [PubMed]
     [Google Scholar]
  153. Vargiu AV, Collu F, Schulz R, Pos KM, Zacharias M et al. Effect of the F610A mutation on substrate extrusion in the AcrB transporter: explanation and rationale by molecular dynamics simulations. J Am Chem Soc 2011; 133:10704–10707 [View Article] [PubMed]
     [Google Scholar]
  154. Yao XQ, Kimura N, Murakami S, Takada S. Drug uptake pathways of multidrug transporter AcrB studied by molecular simulations and site-directed mutagenesis experiments. J Am Chem Soc 2013; 135:7474–7485 [View Article] [PubMed]
     [Google Scholar]
  155. Verchère A, Dezi M, Adrien V, Broutin I, Picard M. In vitro transport activity of the fully assembled MexAB-OprM efflux pump from Pseudomonas aeruginosa. Nat Commun 2015; 6:6890 [View Article] [PubMed]
     [Google Scholar]
  156. Picard M, Tikhonova EB, Broutin I, Lu S, Verchère A et al. Biochemical reconstitution and characterization of multicomponent drug efflux transporters. In Yamaguchi A, Nishino K. eds Bacterial Multidrug Exporters New York, NY: Springer New York; pp 113–145 [View Article]
     [Google Scholar]
  157. Kinana AD, Vargiu AV, May T, Nikaido H. Aminoacyl β-naphthylamides as substrates and modulators of AcrB multidrug efflux pump. Proc Natl Acad Sci U S A 2016; 113:1405–1410 [View Article] [PubMed]
     [Google Scholar]
  158. Masi M, Réfregiers M, Pos KM, Pagès J-M. Mechanisms of envelope permeability and antibiotic influx and efflux in Gram-negative bacteria. Nat Microbiol 2017; 2:17001 [View Article] [PubMed]
     [Google Scholar]
  159. Masi M, Dumont E, Vergalli J, Pajovic J, Réfrégiers M et al. Fluorescence enlightens RND pump activity and the intrabacterial concentration of antibiotics. Res Microbiol 2018; 169:432–441 [View Article] [PubMed]
     [Google Scholar]
  160. Schuster S, Vavra M, Wirth DAN, Kern WV. Comparative reassessment of AcrB efflux inhibitors reveals differential impact of specific pump mutations on the activity of potent compounds. Microbiol Spectr 2024e0304523 [View Article] [PubMed]
     [Google Scholar]
  161. Piddock LJV. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 2006; 19:382–402 [View Article] [PubMed]
     [Google Scholar]
  162. Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 2015; 6:421 [View Article] [PubMed]
     [Google Scholar]
  163. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 2001; 45:105–116 [View Article] [PubMed]
     [Google Scholar]
  164. Kvist M, Hancock V, Klemm P. Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl Environ Microbiol 2008; 74:7376–7382 [View Article] [PubMed]
     [Google Scholar]
  165. Nishino K, Latifi T, Groisman EA. Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol Microbiol 2006; 59:126–141 [View Article] [PubMed]
     [Google Scholar]
  166. Aron Z, Opperman TJ. The hydrophobic trap-the Achilles heel of RND efflux pumps. Res Microbiol 2018; 169:393–400 [View Article] [PubMed]
     [Google Scholar]
  167. Compagne N, Vieira Da Cruz A, Müller RT, Hartkoorn RC, Flipo M et al. Update on the discovery of efflux pump Inhibitors against critical priority Gram-negative bacteria. Antibiotics (Basel) 2023; 12:180 [View Article] [PubMed]
     [Google Scholar]
  168. Renau TE, Léger R, Flamme EM, Sangalang J, She MW et al. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem 1999; 42:4928–4931 [View Article] [PubMed]
     [Google Scholar]
  169. Watkins WJ, Landaverry Y, Léger R, Litman R, Renau TE et al. The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors. Bioorg Med Chem Lett 2003; 13:4241–4244 [View Article] [PubMed]
     [Google Scholar]
  170. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic--A vision for applied use. Biochem Pharmacol 2006; 71:910–918 [View Article] [PubMed]
     [Google Scholar]
  171. Schumacher A, Steinke P, Bohnert JA, Akova M, Jonas D et al. Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Enterobacteriaceae other than Escherichia coli. J Antimicrob Chemother 2006; 57:344–348 [View Article] [PubMed]
     [Google Scholar]
  172. Bohnert JA, Kern WV. Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother 2005; 49:849–852 [View Article] [PubMed]
     [Google Scholar]
  173. Nakayama K, Ishida Y, Ohtsuka M, Kawato H, Yoshida K ichi et al. MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization. Bioorg Med Chem Lett 2003; 13:4201–4204 [View Article] [PubMed]
     [Google Scholar]
  174. Yoshida K-I, Nakayama K, Ohtsuka M, Kuru N, Yokomizo Y et al. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg Med Chem 2007; 15:7087–7097 [View Article] [PubMed]
     [Google Scholar]
  175. Opperman TJ, Kwasny SM, Kim H-S, Nguyen ST, Houseweart C et al. Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrob Agents Chemother 2014; 58:722–733 [View Article] [PubMed]
     [Google Scholar]
  176. Nguyen ST, Kwasny SM, Ding X, Cardinale SC, McCarthy CT et al. Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors. Bioorg Med Chem 2015; 23:2024–2034 [View Article] [PubMed]
     [Google Scholar]
  177. Plé C, Tam H-K, Vieira Da Cruz A, Compagne N, Jiménez-Castellanos J-C et al. Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps. Nat Commun 2022; 13:115 [View Article] [PubMed]
     [Google Scholar]
  178. Vieira Da Cruz A, Jiménez-Castellanos J-C, Börnsen C, Van Maele L, Compagne N et al. Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae. EMBO Mol Med 2024; 16:93–111 [View Article] [PubMed]
     [Google Scholar]
  179. Zhang B, Li J, Yang X, Wu L, Zhang J et al. Crystal structures of membrane transporter MmpL3, an Anti-TB drug target. Cell 2019; 176:636–648 [View Article] [PubMed]
     [Google Scholar]
  180. Li W, Stevens CM, Pandya AN, Darzynkiewicz Z, Bhattarai P et al. Direct inhibition of MmpL3 by novel antitubercular compounds. ACS Infect Dis 2019; 5:1001–1012 [View Article] [PubMed]
     [Google Scholar]
  181. Abdali N, Parks JM, Haynes KM, Chaney JL, Green AT et al. Reviving antibiotics: efflux pump inhibitors that interact with AcrA, a membrane fusion protein of the AcrAB-TolC multidrug efflux pump. ACS Infect Dis 2017; 3:89–98 [View Article] [PubMed]
     [Google Scholar]
  182. Russell Lewis B, Uddin MR, Moniruzzaman M, Kuo KM, Higgins AJ et al. Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein. Nat Commun 2023; 14:3900 [View Article]
     [Google Scholar]
  183. Jiménez-Castellanos J-C, Pradel E, Compagne N, Vieira Da Cruz A, Flipo M et al. Characterization of pyridylpiperazine-based efflux pump inhibitors for Acinetobacter baumannii. JAC Antimicrob Resist 2023; 5:dlad112 [View Article] [PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.001438
Loading
Molecular insights into the determinants of substrate specificity and efflux inhibition of the RND efflux pumps AcrB and AdeB
Microbiology 170, 001438 (2024); https://doi.org/10.1099/mic.0.001438
/content/journal/micro/10.1099/mic.0.001438
/content/journal/micro/10.1099/mic.0.001438
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error