Ebselen and silver has synergistic bactericidal effect
EbsArgent® is a patented combination of ebselen and silver ions that displays strong synergistic bactericidal activity towards a wide range of bacteria, while not being toxic to mammals. Its efficient bacteriocidal activity targets most (if not all) strains of both Gram-positive and Gram-negative bacteria. EbsArgent® asserts its antibacterial activity through a completely novel mechanism of action, explaining its efficacy against the widest variety of bacteria, also including strains resistant towards all other types of antibiotics that have yet been tested. Moreover, it has yet been impossible to develop bacterial strains with resistance against EbsArgent®.
EbsArgent® and its components
Ebselen is a small selenium-containing molecule already evaluated in several clinical trials for treatment of such wide varieties of diseases as brain ischemia and stroke, critical illness, or hearing loss. Most beneficial effects of ebselen in such applications are due to its passing through the blood-brain barrier and acting, in mammalian cells, as an efficient antioxidant compound catalytically propelled by the mammalian thioredoxin and glutathione systems. Ebselen is approved for use in phase III clinical trials (oral administration) and lacks any known toxic side effects at therapeutic doses.
Silver has since ancient times been used as an antibiotic agent and is still included in many antimicrobial formulations, with silver ions being the main antibiotically active form. Its use as an antimicrobial agent in topical applications is well established and considered safe for humans. Silver ions are used in very small amounts in EbsArgent®, enough to exhibit the necessary bactericidal effect, but well below toxicity limits.
The true innovation of EbsArgent® is the groundbreaking discovery by the company founder, late Prof. Arne Holmgren, and his co-workers, that a combination of small amounts of silver nitrate and ebselen gains a remarkably efficient synergistic bactericidal activity. Several studies show that this combination has very limited toxicity to human cells or when evaluated in mouse models of bacterial infections, while EbsArgent® shows promising antibacterial and in some cases life-saving antimicrobial activity.
A new target and novel mechanism of action
The main mechanism of the bactericidal action of EbsArgent® is the irreversible inhibition of bacterial thioredoxin reductase by ebselen, thereby inhibiting this enzyme that is crucial for bacterial survival. Human thioredoxin reductase, on the other hand, is a selenoprotein with a different catalytic mechanism than its prokaryote counterpart. The human enzyme is not inhibited by ebselen but instead supports the antioxidant effects of ebselen in mammalian cells. This qualitative difference explains the much lower toxicity of EbsArgent® towards mammalian cells compared to its bactericidal efficacy. The strong bactericidal synergy of ebselen mixed with silver is due to effects of silver on cell walls of the bacteria, facilitating entry of ebselen into the bacterial cytosol where it subsequently inhibits the bacterial thioredoxin reductase. Several studies have validated the bacterial thioredoxin reductase enzyme as a valid and novel target for antimicrobial therapeutic development. Very importantly, no occurrence of cross-resistance with other antibiotics is seen, likely because the thioredoxin systems is not targeted by any of the current clinically available antibiotics and ebselen is a novel type of molecule compared to other antibiotics. Even silver-resistant bacteria are still susceptible to EbsArgent®, which further confirms its novelty and promising potential in antibacterial therapy.
Clinical target: Urinary tract infection and complicated urinary tract infection
EbsArgent® is currently being developed as a combination drug for treatment of acute and chronic urinary tract infection (UTI) as well as complicated urinary tract infection (cUTI). Its efficacy against both Gram-negative and Gram-positive bacteria, including multidrug-resistant pathogens, highlights its relevancy in these indications. Another notable feature of EbsArgent® is its ability to inhibit biofilm formation, which is a common occurrence in UTIs and a factor often contributing to more persistent infections. Importantly, EbsArgent® has been demonstrated to have high efficacy against all of the bacterial species most commonly causing UTIs and cUTIs, including uropathogenic E. coli (UPEC), K. pneumoniae and Enterococcus spp. Indeed, hundreds of bacterial strains and clinical isolates, of various resistance profiles against other antibiotics, have been tested and all proven susceptible to EbsArgent®.