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Innovative alternatives to antibiotics

Monday 14 July 2014

Development of antimicrobial surfactant to treat patients with cystic fibrosis

Background
Cystic fibrosis (CF) is a life-threatening genetic disorder, primarily characterized by development of chronic pulmonary inflammation and deterioration of pulmonary function. Antibiotic treatment of CF-patients is primarily used to control infections but the emergence of multidrug-resistance underlines the urgent need to develop novel antimicrobial treatment strategies.

Antimicrobial peptides (‘AMPs’, 12-50 amino acids long) are important effector molecules of the innate immune system of vertebrates and exhibit strong antimicrobial properties. Given their potent broad-spectrum antimicrobial properties, AMPs are considered as a promising new class of antibiotics with several major advantages as compared to conventional antibiotics. Importantly, AMPs have shown to be effective against multi-drug resistant bacteria and possess low propensity for developing resistance probably due to their distinguished mode of action. The ability of AMPs to use multiple mechanisms to kill microorganisms (e.g. cell wall permeabilization, inhibition of DNA replication and protein synthesis) has resulted in a growing interest to develop AMP-based strategies to fight infectious diseases in mammals.

Project
This project aims to test the safety and efficacy of a commercially available surfactant (Curosurf®) supplemented with newly designed broad-spectrum AMP derivatives as a novel antimicrobial treatment in CF-patients.

Approach and Methodology
This study will be performed in collaboration with the division of pediatric pulmonology (Wilhelmina Kinderziekenhuis – University Medical Center Utrecht); most experimental work will be carried out at the division of MHD at UU. The first stage of this project aims to investigate the antimicrobial activity of various doses of novel AMPs (and combinations) either in the presence or absence of Curosurf®. In addition, we will study the mechanism by which these AMPs kill microorganisms. This will be tested against a selection of CF-relevant pathogens using a variety of microbiological assays (e.g. colony count assay / spot test / cytotoxicity assays / resistance induction assays / cell line protection assays, others..). The killing potency of AMPs (with or without Curosurf®) and peptide half-life will be tested using sputum samples and nasal swabs derived from CF-patients with established chronic infections. The second stage involves a clinical safety study (Phase 1) of PEPsurf on healthy adults as well as an efficacy study (Phase 2a) of PEPsurf on adult CF-patients. Depending on the start date, the trainee will participate in either stage of this project.

Contact
Martin van Eijk, 030 253 5361, 06 537 35 985, m.vaneijk@uu.nl