ArticleAntimicrobial agents and chemotherapy2015
Two mechanisms of killing of Pseudomonas aeruginosa by tobramycin assessed at multiple inocula via mechanism-based modeling.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 1 of them a synthesis that pooled it.
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Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
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- Recent trends in dual-acting hybrid antibiotics and combination therapies against Gram-negative pathogens.Journal of microbiology (Seoul, Korea) · 2026Review
- The impact of inoculation methods on bacterial aggregation and antimicrobial susceptibility testing.Microbiology (Reading, England) · 2026Article
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- Development of polymyxin- and aminoglycoside-based outer membrane permeabilizers: a review.Frontiers in microbiology · 2025Review
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- Analysis of Antibiotic Response in Clinical Wound Pseudomonas aeruginosa Isolates: Unveiling Proteome Dynamics of Tobramycin-Tolerant Phenotype.Molecular & cellular proteomics : MCP · 2024Article
- Pseudomonas aeruginosa faces a fitness trade-off between mucosal colonization and antibiotic tolerance during airway infection.Nature microbiology · 2024Article
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- Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.Antimicrobial agents and chemotherapy · 2024Article
- New Antimicrobial Strategies to Treat Multi-Drug Resistant Infections Caused by Gram-Negatives in Cystic Fibrosis.Antibiotics (Basel, Switzerland) · 2024Review
- Influence of β-lactam pharmacodynamics on the systems microbiology of gram-positive and gram-negative polymicrobial communities.Frontiers in pharmacology · 2024Article
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Corrections and comments
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Authors and funding
11 authors at 4 institutions in 4 countries.
Funding
Abstract
Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three Pseudomonas aeruginosa strains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 10(8.9) CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.
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