Objective Antibiotic resistance is increasing globally at such a pace that many experts fear the dawn of the post-antibiotic era if we fail to meet the urgent need for novel therapeutics. We evaluated if the working hypothesis of the MANGO ERC project that protein aggregation is driven by sequence specific interactions can be exploited to generate aggregates that are specifically toxic to bacteria without affecting mammalian cells. In particular we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating aggregation in bacteria but not in mammalian cells. Unbiased in vitro screening of aggregating peptides lead to the identification of several hits that are strongly bactericidal against drug resistant gram+ S aureus strains, and others against pathogenic gram- E coli strains. The peptides cured mice from bacterial sepsis without apparent toxic side effects. The peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides and the formation of inclusion bodies. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases that are increasingly threatening global healthcare. However, given the novelty of this concept, the viability of aggregating peptides as antimicrobial therapeutics needs to be further advanced in order to consolidate the already significant interest from the pharmaceutical industry. In the current proposal we outline a series of experiments designed to address some of the key questions that were raised by potential investors and experts from the pharmaceutical sector to whom we presented the current data package. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesmicrobiologybacteriologymedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsmedical and health scienceshealth sciencesinfectious diseasesmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2017-PoC - ERC-Proof of Concept Call for proposal ERC-2017-PoC See other projects for this call Funding Scheme ERC-POC - Proof of Concept Grant Coordinator VIB VZW Net EU contribution € 150 000,00 Address Rijvisschestraat 120 9052 Zwijnaarde - gent Belgium See on map Region Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all VIB VZW Belgium Net EU contribution € 150 000,00 Address Rijvisschestraat 120 9052 Zwijnaarde - gent See on map Region Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
