Empowering antibiotics using host defence peptide to fight antimicrobial resistance in epithelial and systemic infections

Abstract

Antimicrobial host defence peptides (HDPs) show great promise in combating antimicrobial-resistant (AMR) bacteria. However, their use is limited by restricted activity in physiological conditions and cytotoxicity at functional concentrations. A class of synthetic antibacterial and anti-biofilm peptides (SAAPs) with enhanced activity against AMR pathogens has recently been developed to bypass these limitations, particularly in combination with other antibiotics. This project sought to assess the antibacterial activity of a leading candidate, SAAP-148 – and its synergism with antibiotics – across an array of representative in vitro and in vivo models of bacterial infection. Employing and augmenting the high-throughput in vitro model systems of three-dimensional (3D) human skin, lung, and bladder epithelial cultures, and the fruit fly (Drosophila melanogaster) as an in vivo model, respectively, I have: (1) reviewed and analysed the published literature on the combined use of HDPs and antibiotics against AMR bacteria; (2) established the efficacy of SAAP-148 against AMR bacteria in 3D models of infection, including its synergistic interactions with the novel nonpeptide antibiotic halicin; (3) clarified the preventative activity of SAAP-148 against AMR bacteria in skin tissue models, contrasted by its activity in lung tissue models; (4) identified the complementary interactions of SAAP-148 pre-treatment with post-infection halicin in skin and lung tissue models; and (5) developed a dual microinjection model of bacterial infection and antibiotic treatment in D. melanogaster for the assessment of novel therapeutics in vivo. These findings lend support for the use of SAAP-148 as a prophylactic treatment against AMR bacterial infections of the skin, its potential as a synergistic therapeutic in combination with halicin, and the translational utility of D. melanogaster as an in vivo model of both bacterial infection and antibacterial treatment with HDPs.