Aggregatibacter actinomycetemcomitans biofilm killing by a targeted ciprofloxacin prodrug

Benjamin D Reeves,Mark Young,Paul A Grieco,Peter Suci

doi:10.1080/08927014.2013.823541

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.

Highlights

One objective of controlled drug release is to expose pathogens to a sustained lethal dose of an antimicrobial, while minimizing the amount of drug released into the body (Southard &Godowski 1998)
A stable biotinylated fluorescent analogue was synthesized in order to enable visualization of targeting by confocal microscopy and to facilitate determination of the amount of ciprofloxacin prodrug delivered to the biofilms via the biotin-streptavidin couple
The results demonstrate the feasibility of killing a pathogenic biofilm using a targeted cleavable prodrug

Summary

Introduction

The chances of both bacterial resistance and adverse drug reactions are thereby reduced compared to systemic administration (Schwach-Abdellaoui et al 2000; Walker & Karpinia 2002). The localized community structure that endows biofilms with phenotypic drug resistance can be exploited by targeting them with a prodrug that can be triggered to release the free drug. This essentially renders the biofilm itself into a miniature controlled release device. Controlled release is especially relevant as an alternative treatment of periodontitis, a chronic inflammatory condition induced by oral biofilms (Southard & Godowski 1998; Schwach-Abdellaoui, Vivien-Castioni & Gurny 2000). Aggregatibacter actinomycetemcomitans (Aa) is a major risk factor for localized aggressive periodontitis (LAP; Fine et al 2007) and is used to induce the symptomatic chronic inflammatory condition in animal models

Methods

Results

Conclusion