TY - JOUR

T1 - Selective Bacterial Targeting and Infection-Triggered Release of Antibiotic Colistin Conjugates

AU - Tegge, Werner

AU - Guerra, Giulia

AU - Höltke, Alexander

AU - Schiller, Lauritz

AU - Beutling, Ulrike

AU - Harmrolfs, Kirsten

AU - Gröbe, Lothar

AU - Wullenkord, Hannah

AU - Xu, Chunfa

AU - Weich, Herbert

AU - Brönstrup, Mark

N1 - Funding Information: We thank Brigitte Kornak (HZI) for support with peptide synthesis and purification and Prof. Dr. Henk Garritsen from the Institute of Clinical Transfusion Medicine of the Klinikum Braunschweig, Germany, for providing us with plateletpheresis filters. This work was co‐funded by the German Centre for infection research (Grant no TTU09.710), the President's Initiative and Network Fund of the Helmholtz Association of German Research Centres (HGF) under contract number VH‐GS‐202, and the Helmholtz Shandong International Lab. GG received funding from Università Politecnica delle Marche, Ancona. Open access funding enabled and organized by Projekt DEAL.

PY - 2021/8/3

Y1 - 2021/8/3

N2 - 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.

AB - 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.

KW - Antibiotics

KW - drug conjugates

KW - drug delivery

KW - immune activation

KW - natural products

UR - http://www.scopus.com/inward/record.url?scp=85109193520&partnerID=8YFLogxK

U2 - 10.1002/anie.202104921

DO - 10.1002/anie.202104921

M3 - Article

AN - SCOPUS:85109193520

VL - 60

SP - 17989

EP - 17997

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

SN - 1433-7851

IS - 33

ER -