The continuously increasing resistance among bacteria to major antibiotic classes makes infectious diseases one of the most serious public health problems today. Natural host defense peptides with antimicrobial effect has been suggested to be the future of chemotherapeutic therapy. To investigate the pathogenicity of microbial infections and assess the potential of novel candidate drugs, invertebrates has been useful as screening tools providing knowledge of in vivo activities before costly and ethically concerning studies in small mammals. Analogues to mammalians, insects have a highly conserved innate immune system and is at the same time of less ethical concern, low-cost and provide fast turnover results. In this perspective this thesis will examine the utility of the Greater wax moth larvae Galleria mellonella, as a pre-screening tool in the drug development pathway. Novel synthetic GN-peptides were tested against E. coli and two K. pneumoniae isolates whereas the lantibiotic nisin was examined against S. aureus-infected larvae. The pathogenicity of the strains was demonstrated following high bacterial loads (>106 cfu/ml) that caused increased mortality in larvae survival. No peptide compounds had a negative effect on the larvae survival. Furthermore, the utility of this model in antimicrobial efficacy screening was demonstrated here through the assessment of nisin and GN-peptides. The results showed that nisin increased the survival in larvae during S. aureus challenge and GN-2 and GN-4 peptides were capable of rescuing larvae from E. coli infections. In addition, GN-4 peptide also rescued larvae from K. pneumoniae infections. Finally, results from synergy tests indicate a potential for GN-4 peptide as a synergistic agent in combination therapy with tetracycline against K. pneumoniae infections and as an anti-biofilm agent. Hence, as a prove of concept the latter needs future investigations. This infection model is widely used but standardization of protocols in rearing and execution of experiments must be further addressed to obtain inter-laboratory comparable data.
|Uddannelser||Medicinalbiologi, (Bachelor/kandidatuddannelse) Kandidat|
|Udgivelsesdato||28 jun. 2016|