Novel Antimicrobial Hybrid Hydrogel Dressing Targeting Wound Infections Caused by Superbugs Resistant to All Current Antibiotics

This program will develop a 'resistance-proof' antimicrobial hydrogel dressing to prevent and treat wound infections caused by pan-drug-resistant (PDR) bacterial 'superbugs.' The major crosscutting advances in military health and medicine is that this battlefield-ready dressing can be easily applied to keep wounds free from infection and maintain tissue hydration, thereby accelerating the healing process. PDR bacterial infections directly cost the US healthcare system over 20 billion US dollars a year, and it is estimated that PDR infections alone could reduce the world's gross domestic product by 2.24% by 2050. In particular, wound and burn infections are a major medical challenge worldwide due to prevalent antibiotic resistance. The development of a resistance-resistant hydrogel-antibiotic dressing for the prevention and treatment of wound and burn infections caused by bacterial 'superbugs' will undoubtedly result in improved health care on a global scale. This project will identify superior candidates of a new type of antibiotic that bacteria cannot develop resistance to, called teixobactin; and develop suitable hydrogel delivery systems for treatment of wound infections caused by PDR bacterial 'superbugs.' Therefore, there are enormous economic and healthcare benefits associated with our product for active Service members, Veterans, and society. Combat operational trauma is very commonly associated with infections of wounds or other skin structures caused by PDR Gram-negative and Gram-positive bacterial pathogens. In patients with burn injuries, infections caused by the PDR pathogens are associated with significant morbidity and mortality. In a 6-year antibiotic susceptibility records review (2003-2008) at the US Army Institute of Surgical Research Burn Center, Pseudomonas aeruginosa, Acinetobacter baumannii (i.e., 'Iraqibacter'), and Klebsiella pneumonia were the most prevalent organisms recovered. For patients with >60% total body surface area burns, P. aeruginosa was most prevalent. Thus, the discovery of new antibiotics with novel mechanisms of action and a low propensity for resistance development against these dangerous human pathogens is urgently required. One strategy to decrease infections is immediate delivery of antimicrobials at or near the point of injury by the casualty or the first medical responder. For the prevention or treatment of infections after combat-related injuries, it has been highlighted that ideal strategies should be investigated, including novel antimicrobial peptides with broad-spectrum activity, low propensity for resistance, and long duration of action. Our proposed project will develop resistance-proof, broad-spectrum, long-acting teixobactin depsipeptides that are conjugated or combined with lipopeptide potentiators in a hydrogel formulation for delivery against PDR 'superbugs' resistant to all current antibiotics. This antimicrobial dressing will be stable, durable, and suitable for field deployment a part of the combat medics 'tool-kit' in combat situations. Hence, our project is highly significant as it will directly benefit active military Service members and the US Veteran population.