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Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Drug Design and Discovery)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Drug Design and Discovery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Drug Design and Discovery)
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, p. 1346-1360Article in journal (Refereed) Published
Abstract [en]

Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

Place, publisher, year, edition, pages
2018. Vol. 157, p. 1346-1360
Keywords [en]
Antibacterial lipopeptides, Bacterial type I signal peptidase, Escherichia coli type I signal peptidase (EcLepB), P2–P1′ boronic ester-linked macrocycles
National Category
Medicinal Chemistry
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:uu:diva-362335DOI: 10.1016/j.ejmech.2018.08.086ISI: 000447480000096PubMedID: 30196059OAI: oai:DiVA.org:uu-362335DiVA, id: diva2:1253007
Funder
Swedish Research Council, 2014-6711Swedish Research Council, 2015-05406Swedish Research Council, 2017-03953Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-12-11Bibliographically approved

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Lu, LuBenediktsdottir, AndreaZamaratski, EdouardCao, ShaOlanders, GustavKarlen, AndersErdélyi, MátéHughes, DiarmaidMowbray, Sherry LBrandt, Peter

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Lu, LuBenediktsdottir, AndreaZamaratski, EdouardCao, ShaOlanders, GustavKarlen, AndersErdélyi, MátéHughes, DiarmaidMowbray, Sherry LBrandt, Peter
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Department of Medicinal ChemistryStructural BiologyDepartment of Medical Biochemistry and MicrobiologyOrganic ChemistryDepartment of Cell and Molecular Biology
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Medicinal Chemistry

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