This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lomovskaya, O.
Right arrow Articles by Lee, V. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lomovskaya, O.
Right arrow Articles by Lee, V. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 1999, p. 1340-1346, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Use of a Genetic Approach To Evaluate the Consequences of Inhibition of Efflux Pumps in Pseudomonas aeruginosa

Olga Lomovskaya,1,* Angela Lee,1 Kazuki Hoshino,2 Hiroko Ishida,2 Anita Mistry,1 Mark S. Warren,1 Eric Boyer,1 Suzanne Chamberland,1 and Ving J. Lee1

Microcide Pharmaceuticals Inc., Mountain View, California 94043,1 and Daiichi Pharmaceutical Co., Ltd., Tokyo 134, Japan2

Received 11 November 1998/Returned for modification 12 January 1999/Accepted 17 March 1999

Drug efflux pumps in Pseudomonas aeruginosa were evaluated as potential targets for antibacterial therapy. The potential effects of pump inhibition on susceptibility to fluoroquinolone antibiotics were studied with isogenic strains that overexpress or lack individual efflux pumps and that have various combinations of efflux- and target-mediated mutations. Deletions in three efflux pump operons were constructed. As expected, deletion of the MexAB-OprM efflux pump decreased resistance to fluoroquinolones in the wild-type P. aeruginosa (16-fold reduction for levofloxacin [LVX]) or in the strain that overexpressed mexAB-oprM operon (64-fold reduction for LVX). In addition to that, resistance to LVX was significantly reduced even for the strains carrying target mutations (64-fold for strains for which LVX MICs were >4 µg/ml). We also studied the frequencies of emergence of LVX-resistant variants from different deletion mutants and the wild-type strain. Deletion of individual pumps or pairs of the pumps did not significantly affect the frequency of emergence of resistant variants (at 4× the MIC for the wild-type strain) compared to that for the wild type (10-6 to 10-7). In the case of the strain with a triple deletion, the frequency of spontaneous mutants was undetectable (<10-11). In summary, inhibition of drug efflux pumps would (i) significantly decrease the level of intrinsic resistance, (ii) reverse acquired resistance, and (iii) result in a decreased frequency of emergence of P. aeruginosa strains highly resistant to fluoroquinolones in clinical settings.

* Corresponding author. Mailing address: Microcide Pharmaceuticals, Inc., 850 Maude Ave., Mountain View, CA 94043. Phone: (650) 428-3548. Fax: (650) 428-3550. E-mail: olga{at}microcide.com.

Antimicrobial Agents and Chemotherapy, June 1999, p. 1340-1346, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Mima, T., Kohira, N., Li, Y., Sekiya, H., Ogawa, W., Kuroda, T., Tsuchiya, T. (2009). Gene cloning and characteristics of the RND-type multidrug efflux pump MuxABC-OpmB possessing two RND components in Pseudomonas aeruginosa. Microbiology 155: 3509-3517 [Abstract] [Full Text]  
  • Fange, D., Nilsson, K., Tenson, T., Ehrenberg, M. (2009). Drug efflux pump deficiency and drug target resistance masking in growing bacteria. Proc. Natl. Acad. Sci. USA 106: 8215-8220 [Abstract] [Full Text]  
  • Jeannot, K., Elsen, S., Kohler, T., Attree, I., van Delden, C., Plesiat, P. (2008). Resistance and Virulence of Pseudomonas aeruginosa Clinical Strains Overproducing the MexCD-OprJ Efflux Pump. Antimicrob. Agents Chemother. 52: 2455-2462 [Abstract] [Full Text]  
  • Kumar, A., Khan, I. A., Koul, S., Koul, J. L., Taneja, S. C., Ali, I., Ali, F., Sharma, S., Mirza, Z. M., Kumar, M., Sangwan, P. L., Gupta, P., Thota, N., Qazi, G. N. (2008). Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus. J Antimicrob Chemother 61: 1270-1276 [Abstract] [Full Text]  
  • Hocquet, D., Muller, A., Blanc, K., Plesiat, P., Talon, D., Monnet, D. L., Bertrand, X. (2008). Relationship between Antibiotic Use and Incidence of MexXY-OprM Overproducers among Clinical Isolates of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 52: 1173-1175 [Abstract] [Full Text]  
  • Stavri, M., Piddock, L. J. V., Gibbons, S. (2007). Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 59: 1247-1260 [Abstract] [Full Text]  
  • Reinhardt, A., Kohler, T., Wood, P., Rohner, P., Dumas, J.-L., Ricou, B., van Delden, C. (2007). Development and Persistence of Antimicrobial Resistance in Pseudomonas aeruginosa: a Longitudinal Observation in Mechanically Ventilated Patients. Antimicrob. Agents Chemother. 51: 1341-1350 [Abstract] [Full Text]  
  • Dean, C. R., Narayan, S., Richards, J., Daigle, D. M., Esterow, S., Leeds, J. A., Kamp, H., Puyang, X., Wiedmann, B., Mueller, D., Voshol, H., van Oostrum, J., Wall, D., Koehn, J., Dzink-Fox, J., Ryder, N. S. (2007). Reduced Susceptibility of Haemophilus influenzae to the Peptide Deformylase Inhibitor LBM415 Can Result from Target Protein Overexpression Due to Amplified Chromosomal def Gene Copy Number. Antimicrob. Agents Chemother. 51: 1004-1010 [Abstract] [Full Text]  
  • Yan, M., Sahin, O., Lin, J., Zhang, Q. (2006). Role of the CmeABC efflux pump in the emergence of fluoroquinolone-resistant Campylobacter under selection pressure. J Antimicrob Chemother 58: 1154-1159 [Abstract] [Full Text]  
  • Struble, J. M., Gill, R. T. (2006). Reverse Engineering Antibiotic Sensitivity in a Multidrug-Resistant Pseudomonas aeruginosa Isolate.. Antimicrob. Agents Chemother. 50: 2506-2515 [Abstract] [Full Text]  
  • Griffith, D. C., Corcoran, E., Lofland, D., Lee, A., Cho, D., Lomovskaya, O., Dudley, M. N. (2006). Pharmacodynamics of Levofloxacin against Pseudomonas aeruginosa with Reduced Susceptibility Due to Different Efflux Pumps: Do Elevated MICs Always Predict Reduced In Vivo Efficacy?. Antimicrob. Agents Chemother. 50: 1628-1632 [Abstract] [Full Text]  
  • Alyaseen, S. A., Piper, K. E., Rouse, M. S., Steckelberg, J. M., Patel, R. (2005). Selection of Cross-Resistance following Exposure of Pseudomonas aeruginosa Clinical Isolates to Ciprofloxacin or Cefepime. Antimicrob. Agents Chemother. 49: 2543-2545 [Abstract] [Full Text]  
  • Dupont, P., Hocquet, D., Jeannot, K., Chavanet, P., Plesiat, P. (2005). Bacteriostatic and bactericidal activities of eight fluoroquinolones against MexAB-OprM-overproducing clinical strains of Pseudomonas aeruginosa. J Antimicrob Chemother 55: 518-522 [Abstract] [Full Text]  
  • Kriengkauykiat, J., Porter, E., Lomovskaya, O., Wong-Beringer, A. (2005). Use of an Efflux Pump Inhibitor To Determine the Prevalence of Efflux Pump-Mediated Fluoroquinolone Resistance and Multidrug Resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 49: 565-570 [Abstract] [Full Text]  
  • Tikhonova, E. B., Zgurskaya, H. I. (2004). AcrA, AcrB, and TolC of Escherichia coli Form a Stable Intermembrane Multidrug Efflux Complex. J. Biol. Chem. 279: 32116-32124 [Abstract] [Full Text]  
  • Hocquet, D., Bertrand, X., Kohler, T., Talon, D., Plesiat, P. (2003). Genetic and Phenotypic Variations of a Resistant Pseudomonas aeruginosa Epidemic Clone. Antimicrob. Agents Chemother. 47: 1887-1894 [Abstract] [Full Text]  
  • Van Bambeke, F., Glupczynski, Y., Plesiat, P., Pechere, J. C., Tulkens, P. M. (2003). Antibiotic efflux pumps in prokaryotic cells: occurrence, impact on resistance and strategies for the future of antimicrobial therapy. J Antimicrob Chemother 51: 1055-1065 [Full Text]  
  • Mills, S. D. (2003). The role of genomics in antimicrobial discovery. J Antimicrob Chemother 51: 749-752 [Full Text]  
  • Chuanchuen, R., Narasaki, C. T., Schweizer, H. P. (2002). The MexJK Efflux Pump of Pseudomonas aeruginosa Requires OprM for Antibiotic Efflux but Not for Efflux of Triclosan. J. Bacteriol. 184: 5036-5044 [Abstract] [Full Text]  
  • Lin, J., Michel, L. O., Zhang, Q. (2002). CmeABC Functions as a Multidrug Efflux System in Campylobacter jejuni. Antimicrob. Agents Chemother. 46: 2124-2131 [Abstract] [Full Text]  
  • Notka, F., Linde, H.-J., Dankesreiter, A., Niller, H.-H., Lehn, N. (2002). A C-terminal 18 amino acid deletion in MarR in a clinical isolate of Escherichia coli reduces MarR binding properties and increases the MIC of ciprofloxacin. J Antimicrob Chemother 49: 41-47 [Abstract] [Full Text]  
  • Le Thomas, I., Couetdic, G., Clermont, O., Brahimi, N., Plesiat, P., Bingen, E. (2001). In vivo selection of a target/efflux double mutant of Pseudomonas aeruginosa by ciprofloxacin therapy. J Antimicrob Chemother 48: 553-555 [Abstract] [Full Text]  
  • Mao, W., Warren, M. S., Lee, A., Mistry, A., Lomovskaya, O. (2001). MexXY-OprM Efflux Pump Is Required for Antagonism of Aminoglycosides by Divalent Cations in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 45: 2001-2007 [Abstract] [Full Text]  
  • Sulavik, M. C., Houseweart, C., Cramer, C., Jiwani, N., Murgolo, N., Greene, J., DiDomenico, B., Shaw, K. J., Miller, G. H., Hare, R., Shimer, G. (2001). Antibiotic Susceptibility Profiles of Escherichia coli Strains Lacking Multidrug Efflux Pump Genes. Antimicrob. Agents Chemother. 45: 1126-1136 [Abstract] [Full Text]  
  • Lomovskaya, O., Warren, M. S., Lee, A., Galazzo, J., Fronko, R., Lee, M., Blais, J., Cho, D., Chamberland, S., Renau, T., Leger, R., Hecker, S., Watkins, W., Hoshino, K., Ishida, H., Lee, V. J. (2001). Identification and Characterization of Inhibitors of Multidrug Resistance Efflux Pumps in Pseudomonas aeruginosa: Novel Agents for Combination Therapy. Antimicrob. Agents Chemother. 45: 105-116 [Abstract] [Full Text]  
  • Pumbwe, L., Piddock, L. J. V. (2000). Two Efflux Systems Expressed Simultaneously in Multidrug-Resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44: 2861-2864 [Abstract] [Full Text]  
  • Poole, K. (2000). Efflux-Mediated Resistance to Fluoroquinolones in Gram-Negative Bacteria. Antimicrob. Agents Chemother. 44: 2233-2241 [Full Text]  
  • Linde, H.-J., Notka, F., Metz, M., Kochanowski, B., Heisig, P., Lehn, N. (2000). In Vivo Increase in Resistance to Ciprofloxacin in Escherichia coli Associated with Deletion of the C-Terminal Part of MarR. Antimicrob. Agents Chemother. 44: 1865-1868 [Abstract] [Full Text]  
  • Lee, A., Mao, W., Warren, M. S., Mistry, A., Hoshino, K., Okumura, R., Ishida, H., Lomovskaya, O. (2000). Interplay between Efflux Pumps May Provide Either Additive or Multiplicative Effects on Drug Resistance. J. Bacteriol. 182: 3142-3150 [Abstract] [Full Text]  
  • Oethinger, M., Kern, W. V., Jellen-Ritter, A. S., McMurry, L. M., Levy, S. B. (2000). Ineffectiveness of Topoisomerase Mutations in Mediating Clinically Significant Fluoroquinolone Resistance in Escherichia coli in the Absence of the AcrAB Efflux Pump. Antimicrob. Agents Chemother. 44: 10-13 [Abstract] [Full Text]  
  • Westbrock-Wadman, S., Sherman, D. R., Hickey, M. J., Coulter, S. N., Zhu, Y. Q., Warrener, P., Nguyen, L. Y., Shawar, R. M., Folger, K. R., Stover, C. K. (1999). Characterization of a Pseudomonas aeruginosa Efflux Pump Contributing to Aminoglycoside Impermeability. Antimicrob. Agents Chemother. 43: 2975-2983 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»