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

Background: The World Health Organization (WHO) has identified antimicrobial resistance as one of the three greatest threats to human health. In particular, antibiotic-resistant wound infections are a major medical challenge worldwide and represent a considerable healthcare burden. Chronic non-healing and wounds are a major cause high morbidity and mortality in US military personnel and Veterans. Wound infections caused by pan-drug-resistant (PDR) bacterial "superbugs" are immensely concerning as they are resistant to all currently available antibiotics. The Gram-negative wound pathogens Pseudomonas aeruginosa, Acinetobacter baumannii (i.e., "Iraqibacter") and Klebsiella pneumoniae, together with PDR Gram-positive and Staphylococcus aureus, are among the six top-priority dangerous pathogens that require urgent attention for discovery of new antibiotics. Teixobactins are a recently discovered novel antibiotic class that typically possess a narrow spectrum of activity against Gram-positive bacteria. The most notable property of teixobactin is that it is the first and only resistance-resistant antibiotic. Our novel teixobactins are superior to the native compound as they retain this key property and in addition are active against the aforementioned PDR Gram-negatives, as well as PDR Gram-positives. Their therapeutic development will represent a first-in-class, broad-spectrum, resistance-proof antibiotic and a major breakthrough against PDR infections. Objective/Hypothesis: Our overarching hypothesis is that our superior teixobactin-lipopeptide potentiator hydrogel dressing is safe and effective for the prevention and treatment of battlefield wound infections cause by PDR bacterial "superbugs." Our preliminary data show that these superior teixobactins possess improved pharmacological profiles and reduced toxicity compared to native teixobactin and available last-line agents. Our internationally recognized track record in antibiotic discovery, pharmacology, and state-of-the-art facilities for antimicrobial development provide extremely strong support for this project. Specific Aims and Study Design: Our proposed project will develop the first resistance-proof, broad-spectrum, long-acting teixobactin depsipeptides that are conjugated or combined with lipopeptide potentiators in a hydrogel formulation against "superbugs" resistant to all current antibiotics. We will employ a purpose designed funneling approach to identify a candidate (plus one back-up) for preclinical development and Investigational New Drug (IND)-enabling studies. Our specific aims are to: (1) Employ our structure-activity relationships (SAR) model and well-established medicinal chemistry platform to design, synthesize, and microbiologically evaluate approximately 150 novel teixobactin leads focusing on activity against PDR P. aeruginosa, A. baumannii, K. pneumoniae, and S. aureus; and to conduct lead candidate selection based upon (a) in vivo efficacy in a mouse wound infection model, (b) stability in human plasma, (c) toxicity in a mouse model, (d) potential for haemolysis, genotoxicity and cytotoxicity, (e) MICs (minimal inhibitory concentrations) against an extended panel of clinical isolates; (2) develop suitable hydrogel delivery systems for the advanced leads as therapeutics for wound infections caused by these "superbugs"; and (3) evaluate in animal models the safety and efficacy of the superior lead (plus one backup) in the developed hydrogel delivery systems. Relevance, Innovation and Impact: This antimicrobial dressing will be stable, durable, and suitable for field deployment a part of the combat medics "tool-kit" in combat situations. The innovation of our approach lies: Firstly, in the use our novel SAR model and a funneling approach to rationally design and synthesize novel, broad-spectrum teixobactins against the bacteria that are resistant to all current antibiotics. Secondly, application of an antibiotic directly to the infected wound results in higher local concentrations, while minimizing systemic exposure and associated adverse effects. Our novel hydrogel coupling chemistry allows for the controlled and sustained release of high concentrations of antibiotic into the wound, producing rapid bacterial killing at the infection site. In summary, this innovative proposal is of high impact and targets an urgent global and military medical problem: antibiotic-resistant wound infections. Less