Aggregatibacter actinomycetemcomitans biofilm killing by a targeted ciprofloxacin prodrug

Abstract

A pH-sensitive ciprofloxacin prodrug was synthesized and targeted against biofilms of the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa). The dose required to reduce the viability of a mature biofilm of Aa by ∼80% was in the range of ng cm⁻² of colonized area (mean biofilm density 2.33 × 10⁹ cells cm⁻²). A mathematical model was formulated that predicts the temporal change in the concentration of ciprofloxacin in the Aa biofilm as the drug is released and diffuses into the bulk medium. The predictions of the model were consistent with the extent of killing obtained. The results demonstrate the feasibility of the strategy to induce mortality, and together with the mathematical model, provide the basis for design of targeted antimicrobial prodrugs for the topical treatment of oral infections such as periodontitis. The targeted prodrug approach offers the possibility of optimizing the dose of available antimicrobials in order to kill a chosen pathogen while leaving the commensal microbiota relatively undisturbed.

Keywords:

• Aggregatibacter actinomycetemcomitans
• ciprofloxacin
• prodrug
• biofilm
• periodontal disease

Acknowledgements

The authors thank Casey Chen for the Aa strain and for advice on culturing the biofilms. Rudolf Gmür is acknowledged for contributing the Aa antibody. Joseph Seymour is acknowledged for advice on the model. This work was supported by NIH grant 1R21DE019237-01A1 to MY.