Nitric Oxide Functionalized Antibiotics to Combat Infections and Thrombosis for Extracorporeal Life Support

Project Summary/Abstract The major limiting factors to clinical applications of blood-contacting materials, ranging from small catheters to large extracorporeal circulation (ECC) devices, include platelet activation leading to thrombosis and infection. Thrombus formation can further lead to obstruction of blood vessels, device malfunction, or even life-threatening situations such as embolism. Systemic anticoagulation is required to prevent clotting in the devices; however, one of the resulting major complications of this is bleeding. During the COVID-19 pandemic, extracorporeal membrane oxygenation (ECMO) has received critical attention as a therapy for patients where mechanical ventilation alone is ineffective. Significant challenges remain due to the increased risks of thrombosis in the circuitry that can be further exacerbated by hypercoagulable blood exhibited by COVID-19 patients. Therefore, there is an urgent necessity and opportunity to combine strategies for preventing thrombosis and infection into multifunctional device coatings for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymers prevent platelets activation and infection. This technology mimics the vascular endothelial cells lining the blood vessels, as well as other cells in our bodies, producing NO locally to prevent clotting and bacterial biofilm and subsequent infections. Recently we discovered that all of the positive effects can be achieved from polymers physically blended with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Nitric oxide release can prevent platelet activation/adhesion and exhibit broad-spectrum antimicrobial properties, but low NO levels may not completely eradicate the bacterial colonization. Our recent work has shown that by combining active NO release via synthesis of S-nitrosothiol modified ampicillin species when incorporated in medical grade polymers reduces bacterial infection significantly better than NO-releasing polymers alone. The goal of this proposal is to develop, optimize, and evaluate polymer comprised of S- nitrosothiol (RSNO) modified ampicillin (RSNO-icillin) with active NO release (to inhibit platelet adhesion/activation and bactericidal activity) covalently bound to ampicillin (a broad-spectrum antibiotic to ensure eradication of bacteria), resulting in a significantly improved, non-thrombogenic, antimicrobial, and hemocompatible polymer surface. The new polymers will be applicable to any blood- contacting device; however, this proposal will focus on studying the combined antibiotic and NO-releasing strategy in vitro for antimicrobial properties and in a rabbit extracorporeal circulation model for prevention of thrombosis and infection. Successful completion of this project will allow progression to early clinical trials and development of a new generation of extracorporeal circuits that can reduce complications while improving the success of patient care.