The emergence of resistance against current
antibiotics calls for the development of new compounds to treat
infectious diseases. Synthetic pantothenamides are pantothenate analogs that possess broad-spectrum antibacterial activity in vitro in minimal media. Pantothenamides were shown to be substrates of the bacterial
coenzyme A (
CoA) biosynthetic pathway, causing cellular
CoA depletion and interference with
fatty acid synthesis. In spite of their potential use and selectivity for bacterial metabolic routes, these compounds have never made it to the clinic. In the present study, we show that pantothenamides are not active as
antibiotics in the presence of serum, and we found that they were hydrolyzed by ubiquitous pantetheinases of the vanin family. To address this further, we synthesized a series of
pantetheinase inhibitors based on a pantothenate scaffold that inhibited serum
pantetheinase activity in the nanomolar range. Mass spectrometric analysis showed that addition of these
pantetheinase inhibitors prevented hydrolysis of pantothenamides by serum. We found that combinations of these novel
pantetheinase inhibitors and prototypic pantothenamides like N5-Pan and N7-Pan exerted antimicrobial activity in vitro, particularly against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes) even in the presence of serum. These results indicate that pantothenamides, when protected against degradation by host pantetheinases, are potentially useful
antimicrobial agents.