Efflux-Mediated Resistance to Tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1
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Pseudomonas aeruginosa strains are less susceptible to tigecycline (previously GAR-936; MIC, 8 μg/ml) than many other bacteria (P. J. Petersen, N. V. Jacobus, W. J. Weiss, P. E. Sum, and R. T. Testa, Antimicrob. Agents Chemother. 43:738-744, 1999). To elucidate the mechanism of resistance to tigecycline, P. aeruginosa PAO1 strains defective in the MexAB-OprM and/or MexXY (OprM) efflux pumps were tested for susceptibility to tigecycline. Increased susceptibility to tigecycline (MIC, 0.5 to 1 μg/ml) was specifically associated with loss of MexXY. Transcription of mexX and mexY was also responsive to exposure of cells to tigecycline. To test for the emergence of compensatory efflux pumps in the absence of MexXY-OprM, mutants lacking MexXY-OprM were plated on medium containing tigecycline at 4 or 6 μg/ml. Resistant mutants were readily recovered, and these also had decreased susceptibility to several other antibiotics, suggesting efflux pump recruitment. One representative carbenicillin-resistant strain overexpressed OprM, the outer membrane channel component of the MexAB-OprM efflux pump. The mexAB-oprM repressor gene, mexR , from this strain contained a 15-bp in-frame deletion. Two representative chloramphenicol-resistant strains showed expression of an outer membrane protein slightly larger than OprM. The mexCD-OprJ repressor gene, nfxB , from these mutants contained a 327-bp in-frame deletion and an IS element insertion, respectively. Together, these data indicated drug efflux mediated by MexCD-OprJ. The MICs of the narrower-spectrum semisynthetic tetracyclines doxycycline and minocycline increased more substantially than did those of tigecycline and other glycylcyclines against the MexAB-OprM- and MexCD-OprJ-overexpressing mutant strains. This suggests that glycylcyclines, although they are subject to efflux from P. aeruginosa , are generally inferior substrates for P. aeruginosa efflux pumps than are narrower-spectrum tetracyclines.
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MDR efflux pumps AcrAB-TolC in Enterobacteriaceae and MexAB-OprM in P. aeruginosa, both RND-family pumps, extrude tetracyclines including tigecycline as part of their contribution to multidrug resistance.
“In addition to the tetracycline-specific transport systems, several MDR efflux pumps like AcrAB-TolC in Enterobacteriaceae and MexAB-OprM in P. aeruginosa (both belonging to the RND family) are able to extrude tetracyclines (including tigecycline) as part of their contribution to multidrug resistance (48, 49).”
From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [49]
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- Authors
- Dean, C. R., Visalli, M. A., Projan, S. J., Sum, P.-E., & Bradford, P. A.
- Affiliations
- Wyeth (US)
- Corresponding author
- Dean, Charles R.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2003-03
- Volume
- 47
- Issue
- 3
- Pages
- 972-978
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC149306
- OpenAlex
- W2139818499
- Cited by
- 286
- References
- 43
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 13 · 2021: 14 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 6 · 2016: 14 · 2015: 9 · 2014: 8 · 2013: 10 · 2012: 12
- FWCI
- 9.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- tigecycline resistance, Pseudomonas aeruginosa PAO1, efflux pumps, MexXY-OprM, MexCD-OprJ, MexAB-OprM, OprM, mexR, glycylcyclines, tetracycline, doxycycline, minocycline, carbenicillin resistance
- MeSH terms
- Tigecycline, Anti-Bacterial Agents, Bacterial Outer Membrane Proteins, Bacterial Proteins, Culture Media, DNA, Bacterial, Electrophoresis, Polyacrylamide Gel, Microbial Sensitivity Tests, Minocycline, Pseudomonas aeruginosa, Tetracycline Resistance, Tetracyclines, Transcription, Genetic, Blotting, Western, Membrane Transport Proteins
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