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Investigation of a novel target for attenuating bacterial infection
Third-party funded project
Project title Investigation of a novel target for attenuating bacterial infection
Principal Investigator(s) Hevey, Rachel
Project Members Minzer, Giulietta Delia
Organisation / Research unit Departement Pharmazeutische Wissenschaften / Molecular Pharmacy (Ricklin)
Department Departement Pharmazeutische Wissenschaften / Molecular Pharmacy (Ricklin)
Project start 01.09.2020
Probable end 31.08.2021
Status Completed
Abstract

Recent data clearly illustrate the growing threat of infectious pathogens, with nearly 3 million antibiotic-resistant infections recorded annually in the US and 35,000 of these resulting in morbidity. Antibiotic resistance results in failed treatment, prolonged hospital stays, and increases the financial burden placed on the medical system. Therefore, novel approaches to antibiotic use and/or combination therapies are urgently needed.

Recent studies have demonstrated a novel role of mucin glycans in attenuating pathogen virulence in several cross-kingdom species, including Pseudomonas aeruginosa, Candida albicans, and Streptococcus mutans. In a P. aeruginosa porcine burn model, glycan treatment significantly reduced pathogen virulence and increased bacterial susceptibility to host immune defense, thereby indirectly reducing infection load. Based on these observations, a therapeutic molecule which targets the same entity as the mucin glycans would be a promising novel approach to treating infection, and should have a reduced risk of developing resistance as it does not directly affect bacterial survival. This approach to treating infections is highly unconventional as it targets virulence gene regulation rather than pathogen survival.

Given that mucins contain hundreds of different O-glycan structures and therefore their individual glycans cannot be purified from native sources, we have been developing a synthetic platform to access a library of O-glycans and have used this to establish several lead compounds. As mucin glycans are not commercially available, this puts us in the unique position of being able to probe individual molecular interactions and elucidate the unique roles of individual glycan structures. Based on these initial lead compounds, we aim to design, synthesize, and evaluate a series of glycomimetic ligands to assess their potential as novel therapeutics. If successful, this would afford the first example of therapeutically using mucin-derived glycomimetics to attenuate pathogen virulence in infection.

Given the importance of antibiotic-resistance and novel approaches to treating infection, the attenuation of microbial virulence is a promising therapeutic approach as it renders pathogens more susceptible to host immunity. The proposed project will afford a better understanding of mucin-based glycan interactions with pathogens, and early-generation glycomimetics will represent a first class of therapeutic compounds targeting virulence gene suppression.

Keywords antivirulence, glycomimetic, infection, Pseudomonas aeruginosa, lectin
Financed by Swiss National Science Foundation (SNSF)
   

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