Protein aggregation as an antibiotic design strategy
2016 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 99, no 5, 849-865 p.Article in journal (Refereed) PublishedText
Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. 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.
Place, publisher, year, edition, pages
WILEY-BLACKWELL , 2016. Vol. 99, no 5, 849-865 p.
IdentifiersURN: urn:nbn:se:liu:diva-127057DOI: 10.1111/mmi.13269ISI: 000371241600005PubMedID: 26559925OAI: oai:DiVA.org:liu-127057DiVA: diva2:919384
Funding Agencies|VIB; University of Leuven; Funds for Scientific Research Flanders (FWO); Flanders Institute for Science and Technology (IWT); Federal Office for Scientific Affairs of Belgium (Belspo) [IUAP P7/16]; Swedish Foundation for Strategic Research; Swedish Research Council; ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council2016-04-132016-04-132016-04-13