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Development of a Polymicrobial Colony Biofilm Model to Test Antimicrobials in Cystic Fibrosis
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Synergistic Interactions Between the Quinolone-Derived Compound HT61 and Tobramycin Against a Range of Clinical

B Ramsden1, A V Kelis1, M-E Faure1

  • 1Unit of Pulmonary Pharmacology, Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Science, King's College London, Waterloo Campus, 5.72 Franklin-Wilkins Building, London, SE1 9NH, UK.

Lung
|November 27, 2025
PubMed
Abstract

Insights

The antibiotic enhancer HT61 significantly boosted tobramycin's effectiveness against Pseudomonas aeruginosa, a common cause of respiratory infections. This combination shows promise for treating drug-resistant bacterial infections in Cystic Fibrosis and COPD patients.

Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • Antimicrobial resistance in Pseudomonas aeruginosa poses a major threat to patients with respiratory conditions like Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
  • A shortage of effective antibiotics necessitates novel therapeutic strategies, such as antibiotic enhancers that augment existing treatments.
  • HT61, a quinolone-derived compound, has demonstrated the ability to enhance the activity of aminoglycosides like tobramycin and gentamicin against Gram-negative and Gram-positive bacteria.

Purpose of the Study:

  • To investigate the synergistic antimicrobial activity between tobramycin and the enhancer HT61.
  • To evaluate the efficacy of the tobramycin-HT61 combination against a diverse panel of clinical isolates of Pseudomonas aeruginosa from CF patients, including both tobramycin-sensitive and -resistant strains.

Main Methods:

  • Microdilution and chequerboard analyses were employed to assess drug synergy across 63 clinical isolates.
  • Bacterial time-kill assays and biofilm eradication assays were conducted on 13 selected isolates to further characterize the synergistic effects.

Main Results:

  • A significant proportion of isolates (74%, 47/63) exhibited positive interactions or synergy, as indicated by Fractional Inhibitory Concentration Index (FICI) values.
  • The tobramycin-HT61 combination demonstrated augmented antimicrobial activity in time-kill and biofilm eradication assays compared to monotherapy, irrespective of FICI classification.
  • Combination therapy resulted in substantial reductions in bacterial load and biofilm formation.

Conclusions:

  • The findings support the potential of HT61 as an antibiotic enhancer, expanding on previous in vitro studies.
  • The combination of HT61 with tobramycin shows considerable therapeutic promise for managing drug-resistant Pseudomonas aeruginosa infections in respiratory diseases.
  • Further in vivo studies are warranted to fully explore the clinical utility of this combination therapy.
Keywords:
P. aeruginosaAntimicrobial resistanceCombination therapiesRespiratory infectionsSynergy

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