The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration

• Published in: Journal of antimicrobial chemotherapy 2011-04, Vol.66 (4), p.834-839
• Main Authors: LEITNER, I, NEMETH, J, FEURSTEIN, T, ABRAHIM, A, MATZNELLER, P, LAGLER, H, ERKER, T, LANGER, O, ZEITLINGER, M
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Medical sciences; Microbial Sensitivity Tests; Microbial Viability - drug effects; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Quinolines - metabolism; Quinolines - pharmacology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Stenotrophomonas maltophilia; Stenotrophomonas maltophilia - drug effects; Time Factors
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkq526

The use of efflux pump inhibitors may be a powerful strategy to overcome transporter-mediated bacterial multidrug resistance. In the present study, we set out to investigate the potency of tariquidar, a third-generation P-glycoprotein inhibitor in clinical development, for overcoming bacterial resistance towards ciprofloxacin. Staphylococcus aureus 29213 (SA29213) and S. aureus 1199B (SA1199B), which overexpresses the multidrug transporter NorA, as well as Pseudomonas aeruginosa 27853 and Stenotrophomonas maltophilia BAA-85, which expresses SmeDEF, were exposed to ciprofloxacin in the presence and absence of tariquidar or, for comparative reasons, elacridar. Activity of both P-glycoprotein inhibitors was evaluated by determination of MICs and time-kill curves, and by quantification of uptake of ciprofloxacin into bacterial cells. Activity of tariquidar and elacridar was comparable for S. aureus strains, and both dose-dependently increased susceptibility towards ciprofloxacin. Highest effects were observed for SA1199B, where the addition of tariquidar resulted in a 10-fold reduction of the ciprofloxacin MIC, while no effect was observed for P. aeruginosa. For S. maltophilia, elacridar but not tariquidar improved susceptibility. Uptake of [14C]ciprofloxacin and modification of susceptibility showed significant correlations (r=0.89, P