Acute diarrhoeal diseases remain a leading cause of mortality for young children in developing countries - and one of significant morbidity for the international travellers. The spread of enterotoxic multi-drug resistant pathogens among humans is greatly accentuated by long-distance journeys. Yet another important driver for the development and spread of antimicrobial resistance genes is the expanding use of antimicrobials in livestock. Frequent antibiotic therapy in animal husbandry constitutes a problem for the subsequent treatment of human infections for which antimicrobials are being employed, whose profile overlaps with the ones used for farm animals.
Based on the clinical success of our liposomal toxin-sequestering compound CAL02 against staphylococcal and streptococcal toxins (awaiting phase III clinical trial), we have now developed Nanotrap-ET, a novel, broad-spectrum anti-infective compound that neutralizes a whole panoply of toxins released with different kinetics and toxicity profiles by the most frequent and clinically-relevant enteropathogenic bacterial strains. Nanotrap-ET does not affect processes required for bacterial survival per se and has therefore the great advantage of not exerting any selective evolutional pressure promoting the emergence of drug resistance.
Nanotrap-ET has the potential to combat infections caused by the most frequent enteropathogenic bacteria (Escherichia coli, Campylobacter jejuni, Vibrio cholerae, Clostridium difficile) regardless of their antibiotic resistance profile, and is therefore able to be successful against multi and pan-drug resistant strains. This non-bactericidal compound might be readily prescribed before serotyping or antibiogram to promptly avoid tissue damage, promote bacterial clearance, and limit the side effects of adjunctive antimicrobial therapies. Nanotrap-ET is non-toxic, consisting of lipids which occur naturally in the human body.
Quelles sont les particularités de ce projet?
The development of antibiotic resistance is an unintended but unavoidable adverse event of every antibiotic treatment. Therefore, it is now opportune to consider another option: instead of directly killing the bacteria, it might be preferable to limit the damage they induce by their secretion of virulence factors. By neutralizing the bacterial toxins, the pathogen is deprived of its arsenal of weapons and can be eliminated by the infected host’s immune cells without the aid of antibiotics. Since Nanotrap-ET does not come into physical contact with the pathogen, antimicrobial resistance will not develop.
We have engineered a novel liposomal compound, which neutralizes bacterial toxins secreted by enteropathogenic bacteria. Nanotrap-ET protects human immune cells in vitro from the effects of bacterial toxins secreted by Escherichia coli, Campylobacter jejuni, Vibrio cholerae, Clostridium difficile. Animal experiments are in preparation.
Nanotrap-ET is a liquid compound, which will be orally administered. Since product stability beyond the gastric passage needs to be guaranteed, the compound must initially be adsorbed to a carrier substance, which then receives an organic coating with intestinal targeting. In collaboration with Evonik Industries, one of the world’s leading companies for specialty chemicals (Darmstadt, Germany) we are currently developing Nanotrap-ET’s galenic profile.
Anti-toxin therapy is just beginning to show its potential as adjunct or alternative to antibiotics. Natural lipid-based formulae such as our CAL02 or Nanotrap-ET are not likely to elicit adverse reactions. Since they also do not stimulate antimicrobial resistance, they can be administered very early, even before or during diagnostic procedures. It is easy to envisage them as over-the-counter drugs in different preparations: creams and ointments (bacterial superinfections of skin ulcers or burns) toothpaste (acute and chronic gum-infections), pastilles or lozenges (sore throat), capsules (gastrointestinal disorders), sprays (pneumonia and lower respiratory tract infections) or they can be delivered intravenously in septicaemia (CAL02, phase 2 clinical study, Laterre et al, Lancet Inf Dis 2019). A further potential lies in their world wide application in animal husbandry in order to prevent or reduce antibiotic usage and thus diminish the development of resistant pathogens.
The development of CAL02 from initial in vitro experiments into a clinically marketable product was performed within 6 years. Given that the experimental task for Nanotrap-ET and the problem of oral delivery is more complex, we hope to be ready for a phase I clinical study in 2-3 years.
Henry BD, Neill DR, Becker KA ,Gore S, Bricio-Moreno L, Ziobro R, Edwards MJ, Mühlemann K, Steinmann J, Kleuser B, Japtok L, Luginbühl M, Wolfmeier H, Scherag A, Gulbins E, Kadioglu A, Draeger A, Babiychuk EB. Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice. Nature Biotechnology 2015 doi:10.1038/nbt.3037;
Laterre PF, Colin G, Dequin PF, Dugernier T, Boulain T, Azeredo da Silveira S, Lajaunias F, Perez A, François B. CAL02, a novel antitoxin liposomal agent, in severe pneumococcal pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial
, Lancet Infect Dis 2019; 19: 620–30
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Personnes participant au projet
Dernière mise à jour de cette présentation du projet 15.01.2020