Cited by 224Antibiotic Resistance in BacteriaDrug Transport and Resistance MechanismsBacterial Genetics and Biotechnology

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Multidrug Efflux Pump AcrAB of Salmonella typhimurium Excretes Only Those β-Lactam Antibiotics Containing Lipophilic Side Chains

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Nikaido, Hiroshi, Basina, Marina, Nguyen, Vy, Rosenberg, Emiko Y.·1998·Journal of Bacteriology

DOI 10.1128/jb.180.17.4686-4692.1998PMC PMC107484

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Abstract

We found that the previously reported SS-B drug-supersusceptible mutant of Salmonella typhimurium (S. Sukupolvi, M. Vaara, I. M. Helander, P. Viljanen, and P. H. Mäkelä, J. Bacteriol. 159:704–712, 1984) had a mutation in the acrAB operon. Comparison of this mutant with its parent strain and with an AcrAB-overproducing strain showed that the activity of the AcrAB efflux pump often produced significant resistance to β-lactam antibiotics in the complete absence of β-lactamase. The effect of AcrAB activity on resistance was more pronounced with agents containing more lipophilic side chains, suggesting that such compounds were better substrates for this pump. This correlation is consistent with the hypothesis that only those molecules that become at least partially partitioned into the lipid bilayer of the cytoplasmic membrane are captured by the AcrAB pump. According to this mechanism, the pump successfully excretes even those β-lactams that fail to traverse the cytoplasmic membrane, because these compounds are likely to become partitioned into the outer leaflet of the bilayer. Even the compounds with lipophilic side chains were shown to penetrate across the outer membrane relatively rapidly, if the pump was inactivated genetically or physiologically. The exclusion of such compounds, exemplified by nafcillin, from cells of the wild-type S. typhimurium was previously interpreted as the result of poor diffusion across the outer membrane (H. Nikaido, Biochim. Biophys. Acta 433:118–132, 1976), but it is now recognized as the consequence of efficient pumping out of entering antibiotics by the active efflux process.

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Background
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Background
Contribution of Efflux to Cefuroxime Resistance in Clinical Isolates of Escherichia coli
Källman, O., Fendukly, F., Karlsson, I., & Kronvall, G. (2003) · Scandinavian Journal of Infectious Diseases · doi:10.1080/00365540310014639 · Cited by 15
“In a study regarding efflux in Salmonella typhimurium the effect of AcrAB activity on b-lactam resistance was most pronounced with agents containing more lipophilic side-chains (19).”
Background
Permeability of Bacteria to Antibacterial Agents
Nichols, W. W. (2011) · Springer eBooks · doi:10.1007/978-1-4614-1400-1_26 · Cited by 14
Emergence of antibiotic-resistant extremophiles (AREs)
Gabani, P., Prakash, D., & Singh, O. V. (2012) · Extremophiles · doi:10.1007/s00792-012-0475-7 · Cited by 13
A proteomic approach to study Salmonella enterica serovar Typhimurium putative transporter YjeH associated with ceftriaxone resistance
Hu, W. S., Lin, Y.-H., & Shih, C.-C. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.07.090 · Cited by 13
Multidrug Efflux Pumps and Their Inhibitors Characterized by Computational Modeling
Ramaswamy, V. K., Cacciotto, P., Malloci, G., Ruggerone, P., & Vargiu, A. V. (2016) · Springer eBooks · doi:10.1007/978-3-319-39658-3_30 · Cited by 12
Quantifying bacterial efflux within subcellular domains of Pseudomonas aeruginosa
Li, Y., Wilhelm, M. J., Wu, T. H., Hu, X., Ruiz, O. N., & Dai, H. (2024) · Applied and Environmental Microbiology · doi:10.1128/aem.01447-24 · Cited by 11
“Structural biology studies of the RND efflux pump protein (29, 56, 57) in Escherichia coli ( E. coli ), a homolog of MexB in P. aeruginosa , suggest that the pump protein of the efflux pump captures unwanted molecules from both the outer and inner leaflets of the cytoplasmic membrane so that it can…”
Fluoroquinolone Resistance in Salmonella: Mechanisms, Fitness, and Virulence
Li, J., Hao, H., Sajid, A., Zhang, H., & Yuan, Z. (2018) · InTech eBooks · doi:10.5772/intechopen.74699 · Cited by 12
“[48] Nikaido H, Basina M, Nguyen V, Rosenberg EY.”
Background
Noncytotoxic Pyrrolobenzodiazepine–Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis
Picconi, P., Jeeves, R. E., Moon, C., Jamshidi, S., Nahar, K. S., Laws, M., Bacon, J., & Rahman, K. M. (2019) · ACS Omega · doi:10.1021/acsomega.9b00834 · Cited by 11
Bêtalactamines
Cavallo, J.-D., Fabré, R., Jehl, F., Rapp, C., & Garrabé, É. (2004) · EMC-Maladies infectieuses/Encyclopédie médico-chirurgicale. Maladies infectieuses · doi:10.1016/j.emcmi.2004.03.003 · Cited by 11
Computational analysis of structure-based interactions and ligand properties can predict efflux effects on antibiotics
Sarkar, A., Anderson, K. C., & Kellogg, G. E. (2012) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.03.008 · Cited by 10
“In fact, for a long time, the only useful known trait of the AcrA-AcrB-TolC efflux pump was that it transports hydrophobic molecules more easily [24].”
Influential
Engineering Bacterial Efflux Pumps for Solar-Powered Bioremediation of Surface Waters
Kapoor, V. J., & Wendell, D. (2013) · Nano Letters · doi:10.1021/nl400691d · Cited by 10
Region of Heat‐Stable Enterotoxin II of Escherichia coli Involved in Translocation across the Outer Membrane
Okamoto, K., Yamanaka, H., Takeji, M., & Fujii, Y. (2001) · Microbiology and Immunology · doi:10.1111/j.1348-0421.2001.tb02630.x · Cited by 10
Characterization of Clinically Isolated Antibiotic-Resistant Salmonella Typhimurium Exposed to Subinhibitory Concentrations of Ceftriaxone and Ciprofloxacin
Kim, J., & Ahn, J. (2017) · Microbial Drug Resistance · doi:10.1089/mdr.2016.0319 · Cited by 10
“Typhimurium.(29) The tripartite multidrug efflux pump is structurally composed of three essential components, including adaptor AcrA (membrane fusion protein), crystal structure of AcrB (transporter protein), and cylinder-like structure of TolC (outer membrane channel).”
AcrAB Efflux Pump Plays a Crucial Role in Bile Salts Resistance and Pathogenesis of Klebsiella pneumoniae
Shu, R., Liu, G., Xu, Y., Liu, B., Huang, Z., & Wang, H. (2024) · Antibiotics · doi:10.3390/antibiotics13121146 · Cited by 11
Droplet Tn‐Seq identifies the primary secretion mechanism for yersiniabactin in Yersinia pestis
Price, S. L., Thibault, D. M., Garrison, T. M., Brady, A., Guo, H., Kehl‐Fie, T. E., Garneau‐Tsodikova, S., Perry, R. D., van Opijnen, T., & Lawrenz, M. B. (2023) · EMBO Reports · doi:10.15252/embr.202357369 · Cited by 11
“Importantly, AcrAB and other RND efflux systems are also effective mediators of antibiotic resistance (Ma et al , 1994; Nikaido et al , 1998; Riera et al , 2011; Kosmidis et al , 2012; Nowak et al , 2015; Lin et al , 2017) and have previously been targeted to develop drugs that inhibit antibiotic…”
Expression of the Bacillus subtilis TasA signal peptide leads to cell death in Escherichia coli due to inefficient cleavage by LepB
Musik, J. E., Zalucki, Y. M., Day, C. J., & Jennings, M. P. (2021) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2021.183768 · Cited by 9
Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria
Nikaido, H. (2014) · ASM Press eBooks · doi:10.1128/9781555817572.ch19 · Cited by 9
Self-citation
Spatiotemporal expression of the putative MdtABC efflux pump of Phtotorhabdus luminescens occurs in a protease-dependent manner during insect infection
Khattar, Z. A., Lanois, A., Hadchity, L., Gaudriault, S., & Givaudan, A. (2019) · PLoS ONE · doi:10.1371/journal.pone.0212077 · Cited by 9
Multidrug Efflux Pumps in the Genus Erwinia: Physiology and Regulation of Efflux Pump Gene Expression
Thekkiniath, J., Ravirala, R. S., & Francisco, M. S. (2016) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2016.05.011 · Cited by 8
Multidrug efflux systems in Escherichia coli and Enterobacter cloacae obtained from wholesome broiler carcasses
Moreira, M. A. S., Rodrigues, P. P. C. F., Tomaz, R. S., & de Moraes, C. A. (2009) · Brazilian Journal of Microbiology · doi:10.1590/s1517-83822009000200007 · Cited by 8
“coli and it is responsible for the acquisition of multiple antimicrobial resistance, including resistance to tetracycline, chloramphenicol, fluoroquinolones, fusidic acid, lipophilic beta-lactams antibiotics, nalidixic acid, novobiocin and rifamicin (21,22).”
Background
Antimicrobial Drug Efflux Pumps in Salmonella
Nishino, K. (2016) · Springer eBooks · doi:10.1007/978-3-319-39658-3_10 · Cited by 8
Characterization and Molecular Determinants for β-Lactam Specificity of the Multidrug Efflux Pump AcrD from Salmonella typhimurium
Cuesta-Bernal, J., El-Delik, J., Göttig, S., & Pos, K. M. (2021) · Antibiotics · doi:10.3390/antibiotics10121494 · Cited by 8
“Amongst the antimicrobials for which AcrD conferred less susceptibility, lipophilicity showed a wide distribution on the basis of the logarithm of the partition coefficient, logP [34].”
Background
Molecular determinants of antibiotic resistance in Salmonella enterica antibiotic resistance
Pavlova, A. S., Bocharova, Y. A., Kuleshov, K. V., Podkolzin, A. T., & Chebotar, I. V. (2021) · Journal of microbiology epidemiology immunobiology · doi:10.36233/0372-9311-140 · Cited by 7
“enterica реализуется посредством гиперактивности эффлюкс-систем AcrAB-TolC [13, 14].”
Influential
Modeling the Tripartite Drug Efflux Pump Archetype: Structural and Functional Studies of the Macromolecular Constituents Reveal More Than Their Names Imply
Elkins, C. A., & Beenken, K. E. (2005) · Journal of Chemotherapy · doi:10.1179/joc.2005.17.6.581 · Cited by 7
RND/HAE-1 members in the Pseudomonadota phylum: exploring multidrug resistance
Gomes, V. M. S., Bulla, A. C. S., Torres, P. H. M., & da Silva, M. L. (2025) · Biophysical Reviews · doi:10.1007/s12551-025-01297-8 · Cited by 7
The effect of nitric oxide combined with fluoroquinolones against Salmonella enterica serovar Typhimurium in vitro
Çoban, A. Y., & Durupınar, B. (2003) · Memórias do Instituto Oswaldo Cruz · doi:10.1590/s0074-02762003000300023 · Cited by 6
“Nikaido et al. (1998) re- ported that SS-B drug-supersusceptible mutant of S. typhimurium had a mutation in the acrAB operon.”
Background
ThemarRegulon
Barbosa, T. M., & Pomposiello, P. J. (2014) · ASM Press eBooks · doi:10.1128/9781555817572.ch15 · Cited by 6
QSAR Studies on Bacterial Efflux Pump Inhibitors
Thai, K., Do, T.-N., Nguyen, T.-V.-P., Nguyen, D.-K.-T., & Tran, T. (2015) · Advances in chemical and materials engineering book series · doi:10.4018/978-1-4666-8136-1.ch007 · Cited by 5
Creation of Universal Primers Targeting Nonconserved, Horizontally Mobile Genes: Lessons and Considerations
Brown, D. C., & Turner, R. J. (2020) · Applied and Environmental Microbiology · doi:10.1128/aem.02181-20 · Cited by 5
Propargylglycine-based antimicrobial compounds are targets of TolC-dependent efflux systems in Escherichia coli
Roldan, B. J., Pajarillo, A. O., Greenberg, J. D., Karlinsey, J. E., Cafiero, M., Frawley, E. R., & Peterson, L. W. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126875 · Cited by 5
Resistance of Gram-Negative Bacilli to Antimicrobials
Bradford, P. A., & Dean, C. R. (2007) · Springer eBooks · doi:10.1007/978-0-387-72418-8_4 · Cited by 4
Molecular graphics approach to bacterial AcrB protein–β-lactam antibiotic molecular recognition in drug efflux mechanism
Kiralj, R., & Ferreira, M. M. C. (2006) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2005.10.010 · Cited by 4
Active Drug Efflux in Bacteria
Dreier, J. (2014) · ASM Press eBooks · doi:10.1128/9781555815615.ch15 · Cited by 4
Molecular subtyping and antibiotic resistance analysis of Salmonella species
Tatavarthy, A. (2005) · Digital Commons - University of South Florida (University of South Florida) · Cited by 3
Mutation of Aromatic Amino Acid Residues Located at the Amino‐ and Carboxy‐Termini of Escherichia coli Heat‐Stable Enterotoxin Ip Reduces the Efficiency of the Toxin to Cross the Outer Membrane
Yamanaka, H., & Okamoto, K. (2000) · Microbiology and Immunology · doi:10.1111/j.1348-0421.2000.tb02523.x · Cited by 3
Leading articles Antibiotic efflux pumps in prokaryotic cells: occurrence, impact on resistance and strategies for the future of antimicrobial therapy
Françoise Van Bambeke, A., Glupczynski, Y., Plésiat, P., Pechère, J. C., Tulkens, P. M., & Minjoz, J. (2003) · Cited by 2
XCC2366, A Gene Encoding A Putative TetR Family Transcriptional Regulator, is Required for Acriflavin Resistance and Virulence of Xanthomonas campestris pv. campestris
Liao, C., Lo, H., Peng, W.-T., Song, W.-L., Du, S., & Hsiao, Y. (2017) · Current Microbiology · doi:10.1007/s00284-017-1328-5 · Cited by 2
“The acr genes have been documented in several bacteria, such as Edwardsiella tarda [23], Erwinia amylovora [6, 42], Escherichia coli [17, 29, 33, 34, 37, 38, 45], Klebsiella pneumoniae [35, 41, 47], and Salmonella enterica serovar Typhimurium [16, 39, 40].”
Background
Efflux Mediated Co-resistance
Gaurav, A., Sharma, A., & Pathania, R. (2019) · Springer eBooks · doi:10.1007/978-981-13-8503-2_8 · Cited by 2
A Unique Sequence Is Essential for Efficient Multidrug Efflux Function of the MtrD Protein of Neisseria gonorrhoeae
Chitsaz, M., Gupta, V., Harris, B. D. W., O’Mara, M. L., & Brown, M. H. (2021) · mBio · doi:10.1128/mbio.01675-21 · Cited by 2
“Presence of a hydrophobic domain on the molecule or hydrophobicity per se seems to be a common feature of MtrD substrates (7, 45, 46) and suggests that they interact with the IM-periplasm interface before they are captured and exported by MtrD (45).”
Background
Targeted Molecular Dynamics Simulations Suggest Direct Ligand Competition as a Plausible Efflux Inhibition Mechanism in the Multidrug Resistance Pump AcrBPreprint
da Silva, L. V., da Silva, P. E. A., Machado, K., Dutra, N., & Lybrand, T. P. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/339242 · Cited by 2
“285 Independent proposals suggest that AcrB captures ligands directly from the 286 cytoplasm (26) or from the outer leaflet of the cytoplasmic membrane (20).”
Background

Authors: Nikaido, H., Basina, M., Nguyen, V., & Rosenberg, E. Y.
Affiliations: University of California, Berkeley (US)
ORCID: Basina, Marina
Nguyen, Vy
Rosenberg, Emiko Y.
Venue: Journal of Bacteriology
Publisher: American Society for Microbiology
Published: 1998-09
Volume: 180
Issue: 17
Pages: 4686-4692
ISSN: 0021-9193 (ISSN-L)
1098-5530
DOI: 10.1128/jb.180.17.4686-4692.1998
PMC: PMC107484
OpenAlex: W1909542718
Cited by: 224
References: 39
Citations by year: 2026: 1 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 10 · 2018: 10 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 4 · 2013: 4 · 2012: 5
FWCI: 5.93
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Bacteriology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R37AI009644, R01AI009644, AI 09644)
Topics: Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords: AcrAB efflux pump, multidrug efflux, Salmonella typhimurium, beta-lactam antibiotics, antibiotic resistance, lipophilic side chains, membrane partitioning, outer membrane permeability, nafcillin
MeSH terms: Anti-Bacterial Agents, Bacterial Proteins, Cephalosporins, DNA-Binding Proteins, Drug Resistance, Microbial, Microbial Sensitivity Tests, Mutation, Nafcillin, Phenotype, Salmonella typhimurium, Transduction, Genetic

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Multidrug Efflux Pump AcrAB of Salmonella typhimurium Excretes Only Those β-Lactam Antibiotics Containing Lipophilic Side Chains

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