Cited by 165Antibiotic Resistance in BacteriaDrug Transport and Resistance MechanismsBacterial Genetics and Biotechnology

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AcrAB Multidrug Efflux Pump Is Associated with Reduced Levels of Susceptibility to Tigecycline (GAR-936) in Proteus mirabilis

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Visalli, Melissa A., Murphy, Ellen, Projan, Steven J., Bradford, Patricia A.·2003·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.47.2.665-669.2003PMC PMC151746

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Abstract

Tigecycline has good broad-spectrum activity against many gram-positive and gram-negative pathogens with the notable exception of the Proteeae . A study was performed to identify the mechanism responsible for the reduced susceptibility to tigecycline in Proteus mirabilis . Two independent transposon insertion mutants of P. mirabilis that had 16-fold-increased susceptibility to tigecycline were mapped to the acrB gene homolog of the Escherichia coli AcrRAB efflux system. Wild-type levels of decreased susceptibility to tigecycline were restored to the insertion mutants by complementation with a clone containing a PCR-derived fragment from the parental wild-type acrRAB efflux gene cluster. The AcrAB transport system appears to be associated with the intrinsic reduced susceptibility to tigecycline in P. mirabilis .

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Background
Clinical Pharmacokinetics and Pharmacodynamics of Tigecycline
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Tigecycline
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Compound Efflux in Helicobacter pylori
Kutschke, A., & DeJonge, B. L. M. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.7.3009-3010.2005 · Cited by 64
“One of these is the resistance-nodulation-division (RND) family, whose members play a role in the decreased susceptibility to structurally diverse antibacterial compounds in different organisms (4, 5, 7, 8, 11, 12 ).”
Background
Characterization and Sequence Analysis of Extended-Spectrum-β-Lactamase-Encoding Genes from Escherichia coli, Klebsiella pneumoniae , and Proteus mirabilis Isolates Collected during Tigecycline Phase 3 Clinical Trials
Jones, C. H., Tuckman, M., Keeney, D. R., Ruzin, A. V., & Bradford, P. A. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00883-08 · Cited by 61
“Not surprisingly, 52% of the P. mirabilis isolates in the study were resistant to tigecycline; the proposed mechanism for this resistance is upregulation of an efflux pump related to AcrAB (44).”
BackgroundInfluentialSelf-citation
Tigecycline: in-vitro performance as a predictor of clinical efficacy
Hawkey, P. M., & Finch, R. (2006) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2006.01621.x · Cited by 60
“mirabilis [39] and had 81% amino-acid homology.”
BackgroundMethodInfluential
Tigecycline: An investigational glycylcycline antimicrobialwith activity against resistant gram-positive organisms
Garrison, M. W., Neumiller, J. J., & Setter, S. M. (2005) · Clinical Therapeutics · doi:10.1016/j.clinthera.2005.01.007 · Cited by 60
Cloning, Nucleotide Sequencing, and Analysis of the AcrAB-TolC Efflux Pump of Enterobacter cloacae and Determination of Its Involvement in Antibiotic Resistance in a Clinical Isolate
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“It appears that the AcrAB-TolC efflux system in E. cloacae does not pump out fusidic acid, unlike what is seen for other species of Enterobacteriaceae (19, 27).”
BackgroundInfluential
Efflux pumps of Gram-negative bacteria in brief
Auda, I. G., Salman, I. M. A., & Odah, J. G. (2020) · Gene Reports · doi:10.1016/j.genrep.2020.100666 · Cited by 57
Microbiology of drugs for treating multiply drug-resistant Gram-positive bacteria
Eliopoulos, G. M. (2009) · Journal of Infection · doi:10.1016/s0163-4453(09)60004-9 · Cited by 50
Tigecycline: a new glycylcycline antimicrobial
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New advances in antibiotic development and discovery
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“mirabilis [138]) due to the presence of MDR efflux systems.”
Background
Oritavancin and Tigecycline: Investigational Antimicrobials for Multidrug‐Resistant Bacteria
Guay, D. R. P. (2004) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.24.1.58.34808 · Cited by 47
“The reduced intrinsic susceptibility of Proteus mirabilis to tigecycline has been ascribed to the AcrAB multidrug efflux pump.(77) 63”
Background
Anaerobic choline metabolism in microcompartments promotes growth and swarming of P roteus mirabilis
Jameson, E., Fu, T., Brown, I. R., Paszkiewicz, K. H., Purdy, K. J., Frank, S., & Chen, Y. (2015) · Environmental Microbiology · doi:10.1111/1462-2920.13059 · Cited by 47
Induced tigecycline resistance inStreptococcus pneumoniaemutants reveals mutations in ribosomal proteins and rRNA
Lupien, A., Gingras, H., Leprohon, P., & Ouellette, M. (2015) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkv211 · Cited by 46
Real-Time PCR and Statistical Analyses of acrAB and ramA Expression in Clinical Isolates of Klebsiella pneumoniae
Ruzin, A. V., Immermann, F. W., & Bradford, P. A. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00591-08 · Cited by 46
Self-citation
Combined ramR Mutation and Presence of a Tn 1721 -Associated tet (A) Variant in a Clinical Isolate of Salmonella enterica Serovar Hadar Resistant to Tigecycline
Hentschke, M., Christner, M., Sobottka, I., Aepfelbacher, M., & Rohde, H. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00993-09 · Cited by 45
Epidemiological MIC cut-off values for tigecycline calculated from Etest MIC values using normalized resistance interpretation
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RT-PCR and Statistical Analyses of adeABC Expression in Clinical Isolates of Acinetobacter calcoaceticus–Acinetobacter baumannii Complex
Ruzin, A. V., Immermann, F. W., & Bradford, P. A. (2010) · Microbial Drug Resistance · doi:10.1089/mdr.2009.0131 · Cited by 41
Self-citation
Developmental dynamics of antibiotic resistome in aerobic biofilm microbiota treating wastewater under stepwise increasing tigecycline concentrations
Tian, Z., Liu, R., Zhang, H., Yang, M., & Zhang, Y. (2019) · Environment International · doi:10.1016/j.envint.2019.105008 · Cited by 40
Contribution of AcrAB efflux pump to ciprofloxacin resistance in Klebsiella pneumoniae isolated from burn patients
Pakzad, I., Karin, M. Z., Taherikalani, M., Boustanshenas, M., & Lari, A. R. (2013) · Europe PMC (PubMed Central) · doi:10.3205/dgkh000215 · Cited by 37
“pneumoniae [3], [13], [15], [16], [17].”
Tigecycline challenge triggers sRNA production in Salmonella enterica serovar Typhimurium
Yu, J., & Schneiders, T. (2012) · BMC Microbiology · doi:10.1186/1471-2180-12-195 · Cited by 37
“Reports of resistance to tigecycline have been rare in naturally susceptible pathogens, however in resistant variants efflux pump overexpression has contributed to tigecycline resistance [23-28].”
Background
Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?
Athar, M., Gervasoni, S. I., Catte, A., Basciu, A., Malloci, G., Ruggerone, P., & Vargiu, A. V. (2023) · Microbiology · doi:10.1099/mic.0.001307 · Cited by 39
Current and novel antibiotics against resistant Gram-positive bacteria
Pérez, F. (2008) · Infection and Drug Resistance · doi:10.2147/idr.s3545 · Cited by 36
“Although it is known to be inactive against Pseudomonas and Proteus spp. ( Dean et al 2003; Visalli et al 2003), tigecycline held promise as a treatment against multidrug-resistant enterobacteria and Acinetobacter spp.”
Tetracyclines, Glycylcyclines, and Chloramphenicol
Moffa, M. A., & Brook, I. (2015) · Elsevier eBooks · doi:10.1016/b978-1-4557-4801-3.00026-6 · Cited by 40
Analysis of the Topology of Vibrio cholerae NorM and Identification of Amino Acid Residues Involved in Norfloxacin Resistance
Singh, A. K., Haldar, R., Mandal, D., & Kundu, M. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00460-06 · Cited by 36
“Multidrug efflux pumps extrude a variety of structurally unrelated drugs from cells (3, 23, 30), and pumps such as AcrAB have been associated with the intrinsic reduced susceptibility of organisms such as Proteus mirabilis to certain drugs (26, 27, 37 ).”
Background
In vitro activities of tigecycline combined with other antimicrobials against multiresistant Gram-positive and Gram-negative pathogens
Vouillamoz, J., Moreillon, P., Giddey, M., & Entenza, J. M. (2007) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkm459 · Cited by 36
The forgotten Gram-negative bacilli: What genetic determinants are telling us about the spread of antibiotic resistance
Gootz, T. D. (2005) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.11.006 · Cited by 35
Gene interaction network approach to elucidate the multidrug resistance mechanisms in the pathogenic bacterial strain Proteus mirabilis
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Antimicrobial activity against Streptococcus pneumoniae and Haemophilus influenzae collected globally between 2004 and 2008 as part of the Tigecycline Evaluation and Surveillance Trial
Darabi, A., Hocquet, D., & Dowzicky, M. J. (2010) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2009.12.009 · Cited by 34
“; both genera use chromosomally encoded efflux pumps as the mechanism of tigecycline resistance (Dean et al., 2003; Visalli et al., 2003).”
Background
Adaptation of Salmonella enterica Serovar Senftenberg to Linalool and Its Association with Antibiotic Resistance and Environmental Persistence
Kalily, E., Hollander, A., Korin, B., Cymerman, I., & Yaron, S. (2017) · Applied and Environmental Microbiology · doi:10.1128/aem.03398-16 · Cited by 33
In vitro activity of tigecycline against strains isolated from diabetic foot ulcers
Sotto, A., Bouziges, N., Jourdan, N., Richard, J.-L., & Lavigne, J.-P. (2007) · Pathologie Biologie · doi:10.1016/j.patbio.2007.07.003 · Cited by 31
Resistance trends and in vitro activity of tigecycline and 17 other antimicrobial agents against Gram-positive and Gram-negative organisms, including multidrug-resistant pathogens, in Germany
Study Group, Kresken, M., Becker, K., Seifert, H., Leitner, E., Körber-Irrgang, B., von Eiff, C., & Löschmann, P. A. (2011) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-011-1197-y · Cited by 30
“Some taxa, such as Proteus, Providencia, Morganella, Burkholderia cepacia and Pseudomonas aeruginosa, however, show intrinsic reduced susceptibility to tigecycline [14, 15].”
Background
In Vitro Activities of Tigecycline, Ertapenem, Isepamicin,and Other Antimicrobial Agents Against Clinically IsolatedOrganisms in Taiwan
Cheng, N.-C., Hsueh, P., Liu, Y.-C., Shyr, J.-M., Huang, W.-K., Teng, L., & Liu, C. (2005) · Microbial Drug Resistance · doi:10.1089/mdr.2005.11.330 · Cited by 30
“34 In this study, isep-amicin had a similar activity with amikacin against all Enter-obacteriaceae, P. aeruginosa , B. cepacia , and A. baumannii , except for C. freundii isolates in which isepamicin had an eight-fold activity better than amikacin.”
Evaluation of tigecycline activity in clinical isolates among Indian medical centers
Manoharan, A., Chatterjee, S., Madhan, S., & Mathai, D. C. (2010) · Indian Journal of Pathology and Microbiology · doi:10.4103/0377-4929.72061 · Cited by 26
“[6,7] Tigecycline is not recommended for the treatment of infections caused by P.”
Background

Authors: Visalli, M. A., Murphy, E., Projan, S. J., & Bradford, P. A.
Affiliations: Wyeth (US)
Corresponding author: Visalli, Melissa A.
ORCID: Bradford, Patricia A.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2003-02
Volume: 47
Issue: 2
Pages: 665-669
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.47.2.665-669.2003
PMC: PMC151746
OpenAlex: W1976898407
Cited by: 165
References: 25
Citations by year: 2026: 2 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 9 · 2015: 7 · 2014: 2 · 2013: 6 · 2012: 4
FWCI: 7.83
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
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: tigecycline, Proteus mirabilis, AcrAB efflux pump, multidrug efflux, transposon mutants, complementation, tetracycline resistance
MeSH terms: Tigecycline, Carrier Proteins, DNA Transposable Elements, Membrane Proteins, Minocycline, Proteus mirabilis, Drug Resistance, Bacterial, ATP-Binding Cassette, Sub-Family C Proteins, Escherichia coli Proteins

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AcrAB Multidrug Efflux Pump Is Associated with Reduced Levels of Susceptibility to Tigecycline (GAR-936) in Proteus mirabilis

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