Stable pantothenamide bioisosteres: novel antibiotics for Gram-positive bacteria

Patrick A.M. Jansen*, Danique A. van der Krieken, Peter N.M. Botman, Richard H. Blaauw, Lorenzo Cavina, Eline M. Raaijmakers, Erik de Heuvel, Julia Sandrock, Lian J. Pennings, Pedro H.H. Hermkens, Patrick L.J.M. Zeeuwen, Floris P.J.T. Rutjes, Joost Schalkwijk

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)682-692
Number of pages11
JournalJournal of Antibiotics
Issue number9
Publication statusPublished - 1 Sept 2019
Externally publishedYes


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