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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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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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“Indeed, overexpression of the efflux pumps Cdr1, Cdr2, or Mdr1 is a common way adopted by C. albicans to detoxify itself from xenobiotics [100]; P. aeruginosa does the same with MexAB-OprM and MexXY-OprM [101], and S. enterica serovar Typhimurium increases the levels of AcrB to excrete β-lactam antibiotics [102].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [102]
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Substrate-linked Conformational Change in the Periplasmic Component of a Cu(I)/Ag(I) Efflux System
Bagai, I., Liu, W., Rensing, C., Blackburn, N. J., & McEvoy, M. M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703937200 · Cited by 114
Tamura, N., Murakami, S., Oyama, Y., Ishiguro, M., & Yamaguchi, A. (2005) · Biochemistry · doi:10.1021/bi050452u · Cited by 111
Microbial and viral drug resistance mechanisms
McKeegan, K. S., Borges-Walmsley, M. I., & Walmsley, A. R. (2002) · Trends in Microbiology · doi:10.1016/s0966-842x(02)02429-0 · Cited by 111
Pontel, L. B., Audero, M. E. P., Espariz, M., Checa, S. K., & Soncini, F. C. (2007) · Molecular Microbiology · doi:10.1111/j.1365-2958.2007.05963.x · Cited by 108
“Four of them, acrAB, acrD, acrEF and mdtABC, also present in E. coli, affect drug resistance and virulence (Nikaido et al., 1998; Nagakubo et al., 2002; Eaves et al., 2004; Olliver et al., 2005).”
BackgroundMazzariol, A., Cornaglia, G., & Nikaido, H. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.5.1387-1390.2000 · Cited by 105
“The extent of decrease in MIC due to the deletion of acrAB genes in E. coli was very similar to what has been observed in the S. enterica serovar Typhimurium acr mutant SH7616 and generally showed a correlation with the lipophilicity of the side chains (18).”
BackgroundResultInfluentialSelf-citationTruong, Q. C., & Hooper, D. C. (2007) · Journal of Bacteriology · doi:10.1128/jb.01819-06 · Cited by 101
“(16) and represent the calculated octanol-water partition coefficients of the 6-substituents and the 7-substituents of the -lactams.”
BackgroundAdler, M., Anjum, M., Andersson, D. I., & Sandegren, L. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkv475 · Cited by 96
Braoudaki, M. (2004) · FEMS Microbiology Letters · doi:10.1016/j.femsle.2004.04.049 · Cited by 97
Prouty, A. M., van Velkinburgh, J. C., & Gunn, J. S. (2002) · Journal of Bacteriology · doi:10.1128/jb.184.5.1270-1276.2002 · Cited by 95
Lim, S. P., & Nikaido, H. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01714-09 · Cited by 92
“The MICs of the wild-type strains are 512 g/ml (20) or 256 g/ml (12).”
BackgroundInfluentialSelf-citationBraoudaki, M., & Hilton, A. C. (2004) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2004.tb09603.x · Cited by 89
Casin, I., Breuil, J., Darchis, J. P., Guelpa, C., & Collatz, E. (2003) · Emerging infectious diseases · doi:10.3201/eid0911.030317 · Cited by 78
“The high-level resistance to ethidium bromide and the increased susceptibility of the strains to ciprofloxacin in the presence of Phe-Arg-β-naphthylamide were strongly suggestive of an activated drug efflux system, such as AcrAB, the substrates of which also include cephalosporins with lipophilic side chains (2,14).”
BackgroundNikaido, H., & Zgurskaya, H. I. (1999) · Current Opinion in Infectious Diseases · doi:10.1097/00001432-199912000-00001 · Cited by 77
Self-citationVirulence‐targeted Antibacterials: Concept, Promise, and Susceptibility to Resistance Mechanisms
Ruer, S., Pinotsis, N., Steadman, D., Waksman, G., & Remaut, H. K. (2015) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12517 · Cited by 74
Tanmoy, A. M., Westeel, E., Bruyne, K. D., Goris, J., Rajoharison, A., Sajib, M. S. I., van Belkum, A., Saha, S. K., Komurian-Pradel, F., & Endtz, H. P. (2018) · mBio · doi:10.1128/mbio.02112-18 · Cited by 71
A robust platform for chemical genomics in bacterial systems
French, S., Mangat, C. S., Bharat, A., Côté, J., Mori, H., & Brown, E. D. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-08-0573 · Cited by 69
Martı́nez-Martı́nez, L., Pascual, Á., Conejo, M. C., Garcı́a, I., Joyanes, P., Doménech‐Sánchez, A., & Benedi, V. J. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.12.3926-3932.2002 · Cited by 68
Are natural products still the best source for antibacterial discovery? The bacterial entry factor
Silver, L. L. (2008) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.3.5.487 · Cited by 67
“The only apparent substrate specificity for the constitutive pumps of Gram-negatives appears to be presence of a hydrophobic domain (in the substrate molecule) that can be inserted into the CM [57,58,61] .”
BackgroundGayet, S., Chollet, R., Molle, G., Pagès, J., & Chevalier, J. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.5.1555-1559.2003 · Cited by 66
Microdermatology: Cell Surface in the Interaction of Microbes with the External World
Nikaido, H. (1999) · Journal of Bacteriology · doi:10.1128/jb.181.1.4-8.1999 · Cited by 65
“Finally, the presence of certain antibiotics increases the synthesis of efflux pump AcrAB, at the same time decreasing the synthesis of large-channel porin OmpF through the action of the MarA global regulator that was discovered by S. B. Levy; this tends to increase the resistance to antibiotics more effectively by sl…”
BackgroundSelf-citationRybenkov, V. V., Zgurskaya, H. I., Ganguly, C., Leus, I. V., Zhang, Z., & Moniruzzaman, M. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01137 · Cited by 65
Metadata
- Authors
- Nikaido, H., Basina, M., Nguyen, V., & Rosenberg, E. Y.
- Affiliations
- University of California, Berkeley (US)
- 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
- 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
- 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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