Efficient Eradication of Mature Pseudomonas aeruginosa Biofilm via Controlled Delivery of Nitric Oxide Combined with Antimicrobial Peptide and Antibiotics.

Hang Ren,Jianfeng Wu,Alessandro Colletta,Mark E Meyerhoff,Chuanwu Xi

doi:10.3389/fmicb.2016.01260

Hang Ren, Jianfeng Wu + Show 3 more

Open Access

https://doi.org/10.3389/fmicb.2016.01260

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Abstract

Fast eradication of mature biofilms is the ‘holy grail’ in the clinical management of device-related infections. Endogenous nitric oxide (NO) produced by macrophages plays an important role in host defense against intracellular pathogens, and NO is a promising agent in preventing biofilms formation in vitro. However, the rate of delivery of NO by various NO donors (e.g., diazeniumdiolates, S-nitrosothiols, etc.) is difficult to control, which hinders fundamental studies aimed at understanding the role of NO in biofilm control. In this study, by using a novel precisely controlled electrochemical NO releasing catheter device, we examine the effect of physiological levels of NO on eradicating mature Pseudomonas aeruginosa biofilm (7 days), as well as the potential application of the combination of NO with antimicrobial agents. It is shown that physiological levels of NO exhibit mixed effects of killing bacteria and dispersing ambient biofilm. The overall biofilm-eradicating effect of NO is quite efficient in a dose-dependent manner over a 3 h period of NO treatment. Moreover, NO also greatly enhances the efficacy of antimicrobial agents, including human beta-defensin 2 (BD-2) and several antibiotics, in eradicating biofilm and its detached cells, which otherwise exhibited high recalcitrance to these antimicrobial agents. The electrochemical NO release technology offers a powerful tool in evaluating the role of NO in biofilm control as well as a promising approach when combined with antimicrobial agents to treat biofilm-associated infections in hospital settings, especially infections resulting from intravascular catheters.

Highlights

Implanted medical devices are frequently used in hospitals for therapeutic and diagnostic purposes
To study the effect of physiological levels of nitric oxide (NO) on mature biofilm, P. aeruginosa biofilm was allowed to develop on the surface of the catheters for 7 days before NO was turned “on” (NO release profile demonstrated in Supplementary Figure S1)
Our results show that NO release at physiological fluxes is effective in reducing pre-formed biofilms; the used of NO in combination with antimicrobial agents, including antimicrobial peptide and antibiotics, yields an enhancing killing effect

Summary

Introduction

Implanted medical devices are frequently used in hospitals for therapeutic and diagnostic purposes. Antibiotic lock solutions and systemic usage of antibiotics is a common clinical practice (Del Pozo et al, 2012), but biofilm can still form on the devices, and the rate of treatment failure can reach 50% depending. Many studies have focused on the prevention of biofilm formation by obstructing the initial attachment, either by coating antibiotic on the surface or by modifying the physio-chemical properties of the surface (Hasan et al, 2013). These strategies fail to stop the biofilm formation completely as the desired surface property can be dramatically masked or changed in the clinical setting. Strategies to eradicate mature biofilm on medical devices are considered the “holy grail” in controlling biofilm-related infections

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