D. Jones, News and analysis: the antibacterial lead discovery challenge

, Nat RevDrug Discov, vol.9, pp.751-753, 2010.

R. R. Watkins and R. A. Bonomo, Overview: global and local impact of antibiotic resistance, Infect Dis Clin North Am, vol.30, pp.313-335, 2016.

R. Laxminarayan, P. Matsoso, S. Pant, C. Brower, J. A. Røttingen et al., Access to effective antimicrobials: a worldwide challenge, Lancet, vol.387, pp.168-75, 2016.

H. Nikaido, Molecular basis of bacterial outer membrane permeability revisited, Microbiol Mol Biol Rev, vol.67, pp.593-656, 2003.

H. I. Zgurskaya, C. A. López, and S. Gnanakaran, Permeability barrier of Gramnegative cell envelopes and approaches to bypass it, ACS Infect Dis, vol.1, pp.512-522, 2015.

J. M. Pagès, C. E. James, and M. Winterhalter, The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria, Nat Rev Microbiol, vol.6, pp.893-903, 2008.

H. Nikaido, Prevention of drug access to bacterial targets: permeability barriers and active efflux, Science, vol.264, pp.382-390, 1994.

H. Nikaido and J. M. Pagès, Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria, FEMS Microbiol Rev, vol.36, pp.340-63, 2012.

A. Davin-regli, J. M. Bolla, C. E. James, J. P. Lavigne, J. Chevalier et al., Membrane permeability and regulation of drug "influx and efflux" in enterobacterial pathogens, Curr Drug Targets, vol.9, pp.750-759, 2008.

A. Verchère, I. Broutin, and M. Picard, Photo-induced proton gradients for the in vitro investigation of bacterial efflux pumps, Sci Rep, vol.2, p.306, 2012.

A. Verchère, M. Dezi, A. V. Broutin, I. Picard, and M. , vitro transport activity of the fully assembled MexAB-OprM efflux pump from Pseudomonas aeruginosa, vol.6, p.6890, 2015.

T. D. Davis, C. J. Gerry, and D. S. Tan, General platform for systematic quantitative evaluation of small-molecule permeability in bacteria, ACS Chem Biol, vol.9, pp.2535-2579, 2014.

A. R. Brown, K. A. Ettefagh, D. Todd, P. S. Cole, J. M. Egan et al., A mass spectrometry-based assay for improved quantitative measurements of efflux pump inhibition, PLoS ONE, vol.10, p.124814, 2015.

M. F. Richter, B. S. Drown, A. P. Riley, A. Garcia, T. Shirai et al., Predictive compound accumulation rules yield a broad-spectrum antibiotic, Nature, vol.545, pp.299-304, 2017.

D. Jones, News and analysis: the antibacterial lead discovery challenge

, Nat RevDrug Discov, vol.9, pp.751-753, 2010.

R. R. Watkins and R. A. Bonomo, Overview: global and local impact of antibiotic resistance, Infect Dis Clin North Am, vol.30, pp.313-335, 2016.

R. Laxminarayan, P. Matsoso, S. Pant, C. Brower, J. A. Røttingen et al., Access to effective antimicrobials: a worldwide challenge, Lancet, vol.387, pp.168-75, 2016.

H. Nikaido, Molecular basis of bacterial outer membrane permeability revisited, Microbiol Mol Biol Rev, vol.67, pp.593-656, 2003.

H. I. Zgurskaya, C. A. López, and S. Gnanakaran, Permeability barrier of Gramnegative cell envelopes and approaches to bypass it, ACS Infect Dis, vol.1, pp.512-522, 2015.

J. M. Pagès, C. E. James, and M. Winterhalter, The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria, Nat Rev Microbiol, vol.6, pp.893-903, 2008.

H. Nikaido, Prevention of drug access to bacterial targets: permeability barriers and active efflux, Science, vol.264, pp.382-390, 1994.

H. Nikaido and J. M. Pagès, Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria, FEMS Microbiol Rev, vol.36, pp.340-63, 2012.

A. Davin-regli, J. M. Bolla, C. E. James, J. P. Lavigne, J. Chevalier et al., Membrane permeability and regulation of drug "influx and efflux" in enterobacterial pathogens, Curr Drug Targets, vol.9, pp.750-759, 2008.

J. M. Bolla, S. Alibert-franco, J. Handzlik, J. Chevalier, A. Mahamoud et al., Strategies for bypassing the membrane barrier in multidrug resistant Gram-negative bacteria, FEBS Lett, vol.585, pp.1682-90, 2011.
URL : https://hal.archives-ouvertes.fr/hal-01425039

X. Z. Li, P. Plésiat, and H. Nikaido, The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria, Clin Microbiol Rev, vol.28, pp.337-418, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01695304

J. M. Blair, M. A. Webber, A. J. Baylay, D. O. Ogbolu, and L. J. Piddock, Molecular mechanisms of antibiotic resistance, Nat Rev Microbiol, vol.13, pp.42-51, 2015.

R. A. Stavenger and M. Winterhalter, TRANSLOCATION project: how to get good drugs into bad bugs, Sci Transl Med, vol.6, pp.228-235, 2014.

M. Masi, M. Réfrégiers, K. M. Pos, and J. M. Pagès, Mechanisms of envelope permeability and antibiotic influx/efflux in Gram negative bacteria, Nat Microbiol, vol.2, p.17001, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01490432

G. Krishnamoorthy, D. Wolloscheck, J. W. Weeks, C. Croft, V. V. Rybenkov et al., Breaking the permeability Barrier of Escherichia coli by controlled hyperporination of the outer membrane, Antimicrob Agents Chemother, vol.60, pp.7372-81, 2016.

Y. Zhou, C. Joubran, L. Miller-vedam, V. Isabella, A. Nayar et al., Thinking outside the "bug": a unique assay to measure intracellular drug penetration in gram-negative bacteria, Anal Chem, vol.87, pp.3579-84, 2015.

S. Ka??áková, L. Maigre, J. Chevalier, M. Réfrégiers, and J. M. Pagès, Antibiotic transport in resistant bacteria: synchrotron UV fluorescence microscopy to determine antibiotic accumulation with single cell resolution, PLoS ONE, vol.6, p.38624, 2012.

J. M. Pagès, S. Kascàkovà, L. Maigre, A. Allam, M. Alimi et al.,

, New Peptide-based antimicrobials for tackling drug resistance in bacteria: single-cell fluorescence imaging, ACS Med Chem Lett, vol.4, pp.556-565, 2013.

V. Koronakis, A. Sharff, E. Koronakis, B. Luisi, and C. Hughes, Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export, Nature, vol.405, pp.914-923, 2000.

M. F. Symmons, E. Bokma, E. Koronakis, C. Hughes, and V. Koronakis, The assembled structure of a complete tripartite bacterial multidrug efflux pump, Proc Natl Acad Sci U S A, vol.106, pp.7173-7181, 2009.

D. Du, H. W. Van-veen, S. Murakami, K. M. Pos, and B. F. Luisi, Structural and functional aspects of the multidrug efflux pump AcrB, Biol Chem, vol.390, pp.693-702, 2009.

X. Y. Pei, P. Hinchliffe, M. F. Symmons, E. Koronakis, R. Benz et al.,

V. Koronakis, Structures of sequential open states in a symmetrical opening transition of the TolC exit duct, Proc Natl Acad Sci U S A, vol.108, pp.2112-2119, 2011.

P. Hinchliffe, M. F. Symmons, C. Hughes, and V. Koronakis, Structure and operation of bacterial tripartite pumps, Annu Rev Microbiol, vol.67, pp.221-263, 2013.

A. Yamaguchi, R. Nakashima, and K. Sakurai, Structural basis of RND-type multidrug exporters, Front Microbiol, vol.6, p.327, 2015.

R. T. Müller and K. M. Pos, The assembly and disassembly of the AcrAB-TolC three-component multidrug efflux pump, Biol Chem, vol.396, pp.1083-1092, 2015.

L. Daury, F. Orange, J. C. Taveau, A. Verchère, L. Monlezun et al., Tripartite assembly of RND multidrug efflux pumps, Nat Commun, vol.7, p.10731, 2016.
URL : https://hal.archives-ouvertes.fr/hal-02150028

D. Du, Z. Wang, N. R. James, J. E. Voss, E. Klimont et al., Structure of the AcrAB-TolC multidrug efflux pump, Nature, vol.509, pp.512-527, 2014.

S. P. Cohen, D. C. Hooper, J. S. Wolfson, K. S. Souza, L. M. Mcmurry et al., Endogenous active efflux of norfloxacin in susceptible Escherichia coli

, Antimicrob Agents Chemother, vol.32, pp.1187-91, 1988.

S. P. Cohen, L. M. Mcmurry, D. C. Hooper, J. S. Wolfson, and S. B. Levy, Crossresistance to fluoroquinolones in multiple-antibiotic-resistant

, Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction, Antimicrob Agents Chemother, vol.33, pp.1318-1343, 1989.

X. Z. Li, D. M. Livermore, and H. Nikaido, Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin, Antimicrob Agents Chemother, vol.38, pp.1732-1773, 1994.

A. Ocaktan, H. Yoneyama, and T. Nakae, Use of fluorescence probes to monitor function of the subunit proteins of the MexA-MexB-OprM drug extrusion machinery in Pseudomonas aeruginosa, J Biol Chem, vol.272, pp.21964-21973, 1997.

M. Germ, E. Yoshihara, H. Yoneyama, and T. Nakae, Interplay between the efflux pump and the outer membrane permeability barrier in fluorescent dye accumulation in Pseudomonas aeruginosa, Biochem Biophys Res Commun, vol.261, pp.452-457, 1999.

M. Martins, B. Santos, A. Martins, M. Viveiros, I. Couto et al., Management Committee Members; of Cost B16; European Commission/European Science Foundation. An instrument-free method for the demonstration of efflux pump activity of bacteria, In Vivo, vol.20, pp.657-64, 2006.

A. Martins, G. Spengler, M. Martins, L. Rodrigues, M. Viveiros et al., Physiological characterisation of the efflux pump system of antibioticsusceptible and multidrug-resistant Enterobacter aerogenes, Int J Antimicrob Agents, vol.36, pp.313-321, 2010.

M. Martins, M. Viveiros, I. Couto, S. S. Costa, T. Pacheco et al., Identification of efflux pump-mediated multidrug-resistant bacteria by the ethidium bromide-agar cartwheel method, In Vivo, vol.25, pp.171-179, 2011.

M. Martins, M. P. Mccusker, M. Viveiros, I. Couto, S. Fanning et al., A simple method for assessment of MDR bacteria for over-expressed efflux pumps, Open Microbiol J, vol.7, pp.72-82, 2013.

M. Viveiros, A. Martins, L. Paixão, L. Rodrigues, M. Martins et al., Demonstration of intrinsic efflux activity of Escherichia coli K-12 AG100 by an automated ethidium bromide method

, Int J Antimicrob Agents, vol.31, pp.458-62, 2008.

J. A. Bohnert, B. Karamian, and H. Nikaido, Optimized Nile Red efflux assay of AcrAB-TolC multidrug efflux system shows competition between substrates, Antimicrob Agents Chemother, vol.54, pp.3770-3775, 2010.

J. A. Bohnert, S. Schuster, M. Szymaniak-vits, and W. V. Kern, Determination of real-time efflux phenotypes in Escherichia coli AcrB binding pocket phenylalanine mutants using a 1,2'-dinaphthylamine efflux assay, PLoS ONE, vol.6, p.21196, 2011.

J. A. Bohnert, S. Schuster, W. V. Kern, T. Karcz, A. Olejarz et al., Novel piperazine arylideneimidazolones inhibit the AcrAB-TolC pump in Escherichia coli and simultaneously act as fluorescent membrane probes in a combined real-time influx and efflux assay, Antimicrob Agents Chemother, vol.60, pp.1974-83, 2016.

F. Husain and H. Nikaido, Substrate path in the AcrB multidrug efflux pump of Escherichia coli, Mol Microbiol, vol.78, pp.320-350, 2010.

R. Misra, K. D. Morrison, H. J. Cho, and T. Khuu, Importance of real-time assays to distinguish multidrug efflux pump inhibiting and outer membrane destabilizing activities in Escherichia coli, J Bacteriol, vol.197, pp.2479-88, 2015.

K. Nagano and H. Nikaido, Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli, Proc Natl Acad Sci U S A, vol.106, pp.5854-5858, 2009.

S. P. Lim and H. Nikaido, Kinetic parameters of efflux of penicillins by the multidrug efflux transporter AcrAB-TolC of Escherichia coli, Antimicrob Agents Chemother, vol.54, pp.1800-1806, 2010.

A. D. Kinana, A. V. Vargiu, T. May, and H. Nikaido, Aminoacyl ?-naphthylamides as substrates and modulators of AcrB multidrug efflux pump, Proc Natl Acad Sci, vol.113, pp.1405-1410, 2016.

K. Hirai, H. Aoyama, T. Irikura, S. Iyobe, and S. Mitsuhashi, Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli, Antimicrob Agents Chemother, vol.29, pp.535-543, 1986.

K. Hirai, S. Suzue, T. Irikura, S. Iyobe, and S. Mitsuhashi, Mutations producing resistance to norfloxacin in Pseudomonas aeruginosa, Antimicrob Agents Chemother, vol.31, pp.582-588, 1987.

J. S. Chapman and N. H. Georgopapadakou, Fluorometric assay for fleroxacin uptake by bacterial cells, Antimicrob Agents Chemother, vol.33, pp.27-36, 1989.

J. R. De-zeeuw, Accumulation of tetracyclines by Escherichia coli, J Bacteriol, vol.95, pp.498-506, 1968.

P. G. Mortimer and L. J. Piddock, A comparison of methods used for measuring the accumulation of quinolones by Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus, J Antimicrob Chemother, vol.28, pp.639-53, 1991.

J. Chevalier, M. Malléa, and J. M. Pagès, Comparative aspects of the diffusion of norfloxacin, cefepime and spermine through the F porin channel of Enterobacter cloacae, Biochem J, vol.348, pp.223-230, 2000.

S. Baucheron, H. Imberechts, E. Chaslus-dancla, and A. Cloeckaert, The AcrB multidrug transporter plays a major role in high-level fluoroquinolone resistance in Salmonella enterica serovar typhimurium phage type DT204

, Microb Drug Resist, vol.8, pp.281-290, 2002.

E. W. Yu, J. R. Aires, G. Mcdermott, and H. Nikaido, A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study, J Bacteriol, vol.187, pp.6804-6819, 2005.

B. Cinquin, L. Maigre, E. Pinet, C. J. Stavenger, R. A. Mills et al., Microspectrometric insights on the uptake of antibiotics at the single bacterial cell level, Sci Rep, vol.5, p.17968, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01831684

A. Allam, L. Maigre, J. Vergalli, E. Dumont, B. Cinquin et al., Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria, Sci Rep, vol.7, p.986, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01511162

G. Zhao, T. I. Meier, S. D. Kahl, K. R. Gee, and L. C. Blaszczak, Bocillin FL, a sensitive and commercially available reagent for detection of penicillin-binding proteins, Antimicrob Agents Chemother, vol.43, pp.1124-1132, 1999.

Y. Pu, Z. Zhao, Y. Li, J. Zou, Q. Ma et al., Enhanced efflux activity facilitates drug tolerance in dormant bacterial cells, Mol Cell, vol.62, pp.284-94, 2016.

A. Cherkaoui, S. M. Diene, A. Renzoni, S. Emonet, G. Renzi et al., Imipenem heteroresistance in nontypeable Haemophilus influenzae is linked to a combination of altered PBP3, slow drug influx and direct efflux regulation, Clin Microbiol Infect, vol.23, pp.118-127, 2017.

J. Vergalli, E. Dumont, B. Cinquin, L. Maigre, J. Pajovic et al., Fluoroquinolone structure and translocation flux across bacterial membrane, Sci Rep, vol.7, p.9821, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01582320

J. M. Pagès, S. Peslier, T. A. Keating, J. P. Lavigne, and W. W. Nichols, Role of the outer membrane and porins in susceptibility of ?-lactamase-producing Enterobacteriaceae to ceftazidime-avibactam, Antimicrob Agents Chemother, vol.60, pp.1349-59, 2015.

H. Nikaido, Role of permeability barriers in resistance to ß-lactams antibiotics, Pharmac Ther, vol.27, pp.197-231, 1985.

H. Nikaido, Outer membrane barrier as a mechanism of antimicrobial resistance, Antimicrob Agents Chemother, vol.33, pp.1831-1837, 1989.

H. I. Zgurskaya and H. Nikaido, Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli, Proc Natl Acad Sci U S A, vol.96, pp.7190-7195, 1999.

M. Picard, A. Verchère, and I. Broutin, Monitoring the active transport of efflux pumps after their reconstitution into proteoliposomes: caveats and keys, Anal Biochem, vol.420, pp.194-200, 2012.

, vitro investigation of bacterial efflux pumps, Sci Rep, vol.2, p.306, 2012.

A. Verchère, M. Dezi, A. V. Broutin, I. Picard, and M. , vitro transport activity of the fully assembled MexAB-OprM efflux pump from Pseudomonas aeruginosa, vol.6, p.6890, 2015.

T. D. Davis, C. J. Gerry, and D. S. Tan, General platform for systematic quantitative evaluation of small-molecule permeability in bacteria, ACS Chem Biol, vol.9, pp.2535-2579, 2014.

A. R. Brown, K. A. Ettefagh, D. Todd, P. S. Cole, J. M. Egan et al., A mass spectrometry-based assay for improved quantitative measurements of efflux pump inhibition, PLoS ONE, vol.10, p.124814, 2015.

M. F. Richter, B. S. Drown, A. P. Riley, A. Garcia, T. Shirai et al., Predictive compound accumulation rules yield a broad-spectrum antibiotic, Nature, vol.545, pp.299-304, 2017.