Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy

The use of adjuvants that rescue antibiotics against multidrug‐resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β‐lactam antibiotics and β‐lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR ba...

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Bibliographic Details
Published in:Angewandte Chemie 2016-01, Vol.128 (2), p.565-569
Main Authors: Gorityala, Bala Kishan, Guchhait, Goutam, Fernando, Dinesh M., Deo, Soumya, McKenna, Sean A., Zhanel, George G., Kumar, Ayush, Schweizer, Frank
Format: Article
Language:eng ; ger
Subjects:
Adjuvants
Amides
Aminoglykoside
Antibiotics
Antibiotika
Antiinfectives and antibacterials
Bacteria
Chemistry
Ciprofloxacin
Destabilization
Drug resistance
Effectiveness
Fluorchinolone
Inhibitors
Multidrug resistance
Pathogens
Pseudomonas
Pseudomonas aeruginosa
Strategy
Tobramycin
Wirkstoffentwicklung
β-Lactam antibiotics
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Summary:The use of adjuvants that rescue antibiotics against multidrug‐resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β‐lactam antibiotics and β‐lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram‐negative pathogens has been challenging. We describe tobramycin–ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug‐resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure–activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid. Mit Haken und Ösen: Anknüpfen von Tobramycin an Ciprofloxacin liefert Hilfsstoffe, welche die Aktivität von Fluorchinolon‐Antibiotika gegen extrem resistenten Pseudomonas aeruginosa aufrechterhalten. Die Hilfsstoffe kombinieren die antibakterielle Wirkung von Ciprofloxacin mit der Membrandestabilisierung durch Aminoglykoside, um Fluorchinolone und andere Antibiotika leichter in P. aeruginosa einzuschleusen.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201508330