title: Combination of pantothenamides with vanin inhibitors as a novel antibiotic strategy against gram-positive bacteria.
abstract: 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.
authors.affiliation: Department of Dermatology and Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Patrick A M
authors.initials: PA
authors.lastname: Jansen
authors.forename: Pedro H H
authors.initials: PH
authors.lastname: Hermkens
authors.forename: Patrick L J M
authors.initials: PL
authors.lastname: Zeeuwen
authors.forename: Peter N M
authors.initials: PN
authors.lastname: Botman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Blaauw
authors.forename: Peter
authors.initials: P
authors.lastname: Burghout
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Galen
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.forename: Floris P J T
authors.initials: FP
authors.lastname: Rutjes
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010205:Pantothenic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D010205:Pantothenic Acid