Abstract
In order to render potent, but toxic antibiotics more selective, we have explored a novel conjugation strategy that includes drug accumulation followed by infection‐triggered release of the drug. Bacterial targeting was achieved using a modified fragment of the human antimicrobial peptide ubiquicidin, as demonstrated by fluorophore‐tagged variants. To limit the release of the effector colistin only to infection‐related situations, we introduced a linker that was cleaved by neutrophil elastase (NE), an enzyme secreted by neutrophil granulocytes at infection sites. The linker carried an optimized sequence of amino acids that was required to assure sufficient cleavage efficiency. The antibacterial activity of five regioisomeric conjugates prepared by total synthesis was masked, but was released upon exposure to recombinant NE when the linker was attached to amino acids at the 1‐ or the 3‐position of colistin. A proof‐of‐concept was achieved in co‐cultures of primary human neutrophils and Escherichia coli that induced the secretion of NE, the release of free colistin, and an antibacterial efficacy that was equal to that of free colistin.
Highlights
Infections by multidrug-resistant bacteria have been recognized as a global threat to human health.[1]
Because all attempts to connect Ubi29–41 as a C-terminal thioester to a cysteine-modified elastase substrate by native chemical ligation failed, a copper-catalyzed alkyne–azide cycloaddition reaction was applied for coupling
We have validated a new concept for antibiotic conjugates that are activated by the pathogen at the site of infection
Summary
Infections by multidrug-resistant bacteria have been recognized as a global threat to human health.[1]. We would like to present a novel concept to improve the therapeutic window of highly potent, and toxic antibiotics like colistin by selectively enhancing their concentration at the pathogen, while minimizing the (toxic) exposure to host cells. For this purpose, a drug conjugation approach[14] was applied to introduce two additional functionalities to 1: - A targeting moiety should direct the antibiotic effector to bacterial cells - The release of the effector should be triggered selectively at the site of infection. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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