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Enhancing outer membrane permeability of tetracycline antibiotics in P. aeruginosa using TOB-CIP conjugates
Shiv Dhiman1, Danyel Ramirez1, Rajat Arora1
1Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada Frank.Schweizer@umanitoba.ca.
Abstract:
Pseudomonas aeruginosa is an opportunistic critical 'priority 1' Gram-negative bacterium that poses a severe threat to public healthcare due to rising antibiotic resistance. Particularly, low membrane permeability and overexpression of efflux pumps in P. aeruginosa lead to intrinsic resistance that compromises the antibacterial activity of antibiotics. The broad-spectrum antibiotics class, tetracyclines, are rarely used to treat P. aeruginosa infections. In the present study, we describe a series of tobramycin-ciprofloxacin (TOB-CIP) conjugates in which the carboxylic acid of ciprofloxacin is linked to the aminoglycoside tobramycin using various tethers thereby generating a cationic amphiphile. The emerging amphiphilic conjugates potentiate tetracycline antibiotics including minocycline, doxycycline, tigecycline, and eravacycline against multidrug-resistant P. aeruginosa isolates. The structure-activity relationship investigation indicates that the flexible hydrophobic C12 carbon-chain linker in TOB-CIP conjugate 1a is an optimal potentiator of tetracyclines against tetracycline-resistant and -susceptible strains of P. aeruginosa. Furthermore, conjugate 1a consistently synergized with the 3rd generation tetracycline, eravacycline, in P. aeruginosa PAO1 in the presence of up to 25% fetal bovine serum (FBS).
Insights
New tobramycin-ciprofloxacin (TOB-CIP) conjugates enhance tetracycline effectiveness against drug-resistant Pseudomonas aeruginosa. The C12-linked conjugate 1a shows optimal potentiation, even in challenging conditions like fetal bovine serum.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Antimicrobial Resistance
Background:
- Pseudomonas aeruginosa is a critical priority Gram-negative bacterium with significant antibiotic resistance.
- Intrinsic resistance mechanisms like low membrane permeability and efflux pumps limit antibiotic efficacy.
- Tetracyclines are seldom used for P. aeruginosa due to these resistance challenges.
Purpose of the Study:
- To develop novel tobramycin-ciprofloxacin (TOB-CIP) conjugates to overcome P. aeruginosa antibiotic resistance.
- To investigate the structure-activity relationship of these conjugates as potentiators of tetracycline antibiotics.
- To evaluate the efficacy of the most promising conjugate in relevant biological conditions.
Main Methods:
- Synthesis of tobramycin-ciprofloxacin conjugates with varying tethers.
- Evaluation of conjugate activity against multidrug-resistant P. aeruginosa isolates.
- Structure-activity relationship analysis to identify optimal linker characteristics.
- Assessment of conjugate synergy with tetracyclines, including eravacycline, in the presence of fetal bovine serum.
Main Results:
- Novel cationic amphiphilic TOB-CIP conjugates were successfully synthesized.
- These conjugates potentiated various tetracyclines against multidrug-resistant P. aeruginosa.
- Conjugate 1a, featuring a C12 linker, demonstrated optimal potentiation of tetracyclines.
- Conjugate 1a showed consistent synergy with eravacycline in P. aeruginosa PAO1, even with 25% FBS.
Conclusions:
- Tobramycin-ciprofloxacin conjugates represent a promising strategy to enhance tetracycline activity against P. aeruginosa.
- The C12 linker in conjugate 1a is crucial for its potentiating effect.
- Conjugate 1a offers a potential solution for treating infections caused by resistant P. aeruginosa strains, even in complex biological environments.
