Thomas Thyge Thomsen:
Peptide antibiotics for ESKAPE pathogens

Date: 04-01-2016    Supervisor: Kim Rewitz & Anders Løbner-Olesen

Multi-drug resistance to antibiotics represents a global health challenge that results in increased morbidity and mortality rates. The annual death-toll is >700.000 people world-wide, rising to ~10 million by 2050. New antibiotics are lacking, and few are under development as return on investment is considered poor compared to medicines for lifestyle diseases. According to the WHO we could be moving towards a post-antibiotic era in which previously treatable infections become fatal. Of special importance are multidrug resistant bacteria from the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter, Pseudomonas aeruginosa and Enterobacter). As a consequence of widespread multi-drug resistance, researchers have sought for alternative sources of antimicrobials. Antimicrobial peptides are produced by almost all living organisms as part of their defense or innate immune system and are therefore of interest for development of novel antimicrobials.

This thesis aimed at developing new or improved peptide-based antimicrobials, capable of killing or inhibiting the proliferation of important multidrug resistant bacteria. Further we sought to analyze in vivo efficacy and toxicity by utilizing of the fruit fly Drosophila melanogaster as a whole animal model. This was carried out by testing of antimicrobial peptides targeting Gram-positive bacteria exemplified by the important human pathogen methicillin resistant S. aureus (MRSA).

The peptide BP214 was developed from a cecropin-mellitin hybrid peptide and proved effective in killing colistin resistant Gram-negative A. baumannii in vitro. The molecule was improved with regard to toxicity, as measured by hemolytic ability. Further, this peptide is capable of specifically killing non-growing cells of colistin resistant A. baumannii, also known as persisters.

Using D. melanogaster as an in vivo efficacy model it was demonstrated that the Lantibiotic NAI- 107, currently undergoing pre-clinical studies, rescues D. melanogaster from MRSA infection with similar efficacy to last resort antimicrobial vancomycin. Furthermore, it was shown that this antimicrobial has similar capability to BP214 in killing non-growing cells of S. aureus. However, for NAI-107 this is independent of genotype and underscores its potential for future development.