Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and β-Lactam Antibiotics against Multidrug-Resistant <i>Pseudomonas aeruginosa</i>
Bibliographic record
Abstract
According to the World Health Organization, antibiotic resistance is a global health threat. Of particular importance are infections caused by multidrug-resistant Gram-negative bacteria including Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa for which limited treatment options exist. Multiple and simultaneously occurring resistance mechanisms including outer membrane impermeability, overexpression of efflux pumps, antibiotic-modifying enzymes, and modification of genes and antibiotic targets have made antibiotic drug development more difficult against these pathogens. One strategy to cope with these challenges is the use of outer membrane permeabilizers that increase the intracellular concentration of antibiotics when used in combination. In some circumstances, this approach can rescue antibiotics from resistance or repurpose currently marketed antibiotics. Tobramycin-based hybrid antibiotic adjuvants that combine two outer membrane-active components have been previously shown to potentiate antibiotics by facilitating transit through the outer membrane, resulting in increased antibiotic accumulation within the cell. Herein, we extended the concept of tobramycin-based hybrid antibiotic adjuvants to tobramycin-based chimeras by engineering up to three different membrane-active antibiotic warheads such as tobramycin, 1-(1-naphthylmethyl)-piperazine, ciprofloxacin, and cyclam into a central 1,3,5-triazine scaffold. Chimera 4 (TOB-TOB-CIP) consistently synergized with ciprofloxacin, levofloxacin, and moxifloxacin against wild-type and fluoroquinolone-resistant P. aeruginosa . Moreover, the susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached using the triple combination of chimera 4 with ceftazidime/avibactam, aztreonam/avibactam, and imipenem/relebactam, respectively, against β-lactamase-harboring P. aeruginosa . Our findings demonstrate that tobramycin-based chimeras form a novel class of antibiotic potentiators capable of restoring the activity of antibiotics against P. aeruginosa .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".