Microneedle delivery of non-ribosomal antimicrobial peptides to treat multidrug-resistant Gram-negative infections

The increasing prevalence of infections caused by multidrug-resistant (MDR) bacteria is a major global concern, with global deaths due to antimicrobrial resistance expected to hit ten million per year by 2050. Gram-negative bacteria are particularly problematic as their outer-membrane renders them immune to many antibiotics, and the World Health Organization has designated the Gram-negative pathogens carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii as critical targets. We need novel antibiotics and treatments.

Non-ribosomal antibacterial peptides (NRAPs) are a class of compounds that have found special use in the treatment of MDR bacteria. For example, colistin is a last resort antibiotic for the treatment of MDR P. aeruginosa, Klebsiella pneumoniae and Acinetobacter infections, and daptomycin is a key antibiotic for treating MDR enterococci. They typically kill bacteria through interactions with non-protein membrane targets, and are therefore less susceptible to many common resistance mechanisms. However, NRAPs like colistin can cause neurotoxicity and nephrotoxicity when administered intravenously. An alternative, slow release method may circumvent this problem, providing a novel treatment against critical priority pathogens. Microneedle arrays allow delivery of injectable medicines through the skin without causing pain or bleeding. They are self-applied by the patient and can be designed to sustain release over several days

This interdisciplinary project will involve peptide synthesis, polymer synthesis, antimicrobial efficacy assays and pharmacokinetic/pharmacodynamic studies. A series of novel NRAPs will be chemically synthesized and tested in advanced in vitro biological models to ascertain their efficacy against MDR Gram-negative bacteria and safety with respect to normal human cells. In vivo animal pharmacokinetic and infection studies will demonstare the clinical potential of these novel NRAP-microneedle combinations.