Combination of Pantothenamides with Vanin Inhibitors as a Novel Antibiotic Strategy against Gram-Positive Bacteria

Abstract

eThe 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 Grampositive 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. There is a continuous battle between humans and microorganisms, and the development of resistance against current antibiotics creates a need to develop new drug scaffolds and targets (1). There are several classes of antibiotic-resistant pathogens that are emerging as major threats. Methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains (MRSA and VRSA) and multidrug-resistant Streptococcus pneumoniae are serious health problems in both hospital settings and the community. Multidrug-resistant Gram-negative bacteria (e.g., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) are a second group of organisms that pose a threat of untreatable infections. Finally, poverty-related conditions such as tuberculosis and parasitic diseases, which are particularly important in developing countries, are a cause of great concern, as the already-limited number of treatment modalities is decreasing because of resistance. The development of new antibiotics has been slow, and most compounds to date have been derived from a limited number of molecular scaffolds targeting a few microbial molecular pathways. Discovery of new scaffolds and new targets should clearly be a priority, although the commercial prospects of antibiotic development are unfavorable (1).In 1970, amides derived from pantothenic acid (vitamin B5), were reported to possess antibiotic activity in vitro (2). During the last few decades, many of these pantothenamides have been synthesized and the pu...

The Effects of Vitamin B in Depression

“…Excretion of pantothenic acid occurs mostly in the urine, as free pantothenic acid and some 4'-phosphopanthenate, however 15% of pantothenic acid is also oxidized and excreted through the lungs as CO2. Several studies to date have reported that amides derived from pantothenic acid possess an antibiotic quality within the body, which may prove to be a novel antibiotic solution to appropriately relevant gram positive bacteria [92] or malarial agents [93]. Higher levels of nutrient intake, including pantothenic acid, results in better mental health scores, as based on the global assessment of functioning scores and the Hamilton depression rating scale [39].…”

Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides

“…Many pantothenamides tested to date are degraded by the enzyme pantetheinase (vanin) [41,46,49,50] into pantothenate and the corresponding amine (blue shading), and thereby rendered ineffective as pantothenate antivitamins [41,49,50].…”

“…Two strategies have been put forward to overcome this pantetheinase-mediated degradation and thus enable the pantothenamides to exert their antimicrobial effect: (i) inhibition of pantetheinases by potent and specific inhibitors, such as compound RR6 (purple shading) [50], and (ii) modification of the pantothenamide core structure to render the compounds resistant to degradation while maintaining their antimicrobial activity (green shading) [49]. Both strategies appear to be effective in vitro and both offer distinct advantages and disadvantages.…”

“…The first [49] involves structural modification of pantothenamides to yield compounds that are poor substrates of pantetheinases (or do not interact with pantetheinases at all) and yet continue to make the interactions required for their antiplasmodial effect. The second [50] involves the simultaneous addition of exquisitely potent and specific pantetheinase inhibitors (e.g. compound RR6; see Figure 3 for structure) [51].…”

“…N-phenethylpantothenamide, which inhibits parasite growth with low-nanomolar potency) are available and ready to be tested in combination with pantheinase inhibitors in animal models. Jansen et al [50] have shown recently that at least in vitro, pantetheinase inhibitors can effectively protect pantothenamides (e.g. N5-Pan) from pantetheinase-mediated degradation in the presence of serum and restore the full potency of the compounds against bacteria.…”