Stable pantothenamide bioisosteres: novel antibiotics for Gram-positive bacteria

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Abstract

The emergence of multidrug resistant bacteria has prioritized the development of new antibiotics. N-substituted pantothenamides, analogs of the natural compound pantetheine, were reported to target bacterial coenzyme A biosynthesis, but these compounds have never reached the clinic due to their instability in biological fluids. Plasma-stable pantothenamide analogs could overcome these issues. We first synthesized a number of bioisosteres of the prototypic pantothenamide N7-Pan. A compound with an inverted amide bond (CXP18.6-012) was found to provide plasma-stability with minimal loss of activity compared to the parent compound N7-Pan. Next, we synthesized inverted pantothenamides with a large variety of side chains. Among these we identified a number of novel stable inverted pantothenamides with selective activity against Gram-positive bacteria such as staphylococci and streptococci, at low micromolar concentrations. These data provide future direction for the development of pantothenamides with clinical potential.

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Author and article information

Contributors

Patrick A. M. Jansen: Patrick.jansen@radboudumc.nl

Joost Schalkwijk: Joost.schalkwijk@radboudumc.nl

Journal

Journal ID (nlm-ta): J Antibiot (Tokyo)

Journal ID (iso-abbrev): J. Antibiot

Title: The Journal of Antibiotics

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0021-8820

Publication date (Electronic): 6 June 2019

Publication date PMC-release: 6 June 2019

Publication date (Print): 2019

Volume: 72

Issue: 9

Pages: 682-692

Affiliations

[1 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Dermatology, , Radboud University Medical Center, ; Nijmegen, The Netherlands

[2 ]Chiralix, Nijmegen, The Netherlands

[3 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Medical Microbiology, , Radboud University Medical Center, ; Nijmegen, The Netherlands

[4 ]Hermkens Pharma Consultancy, Oss, The Netherlands

[5 ]ISNI 0000000122931605, GRID grid.5590.9, Institute for Molecules and Materials, , Radboud University, ; Nijmegen, The Netherlands

Article

Publisher ID: 196

DOI: 10.1038/s41429-019-0196-6

PMC ID: 6760626

PubMed ID: 31171848

SO-VID: f5b33526-c866-48e3-9a1c-bff29d02504e

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.