Orally-active Biomimetic-polymers TArgeting C. difficile – OBTAC

Clostridioides difficile (C. difficile) is a toxigenic bacterium responsible for severe nosocomial intestinal infections. About 500.000 patients are infected every year in the USA, causing 13.000 deaths, according to the American CDC. To treat such intestinal infections, only 2 antibiotics are recommended as first line oral treatments, exposing to a 15-25% risk of resistance and infection recurrences. Regarding phase III clinical trials, only 1 molecule is being studied against C. difficile, worrying situation which explains why this pathogen was listed among the 5 urgent bacterial threats by the CDC. To develop new orally-active antibiotics against C. difficile, cationic amphiphilic antimicrobial peptides (AMP) are quite inspiring natural antibiotics which present several advantages: i) their mechanism of action is different from the ones of commercial anti-C. difficile antibiotics, ii) their capacity to disrupt the membrane/cell wall exposes to a lower risk of resistance and iii) their peptidic structure allows a rapid degradation in the environment, limiting the risk of selection of resistant bacteria. Nevertheless, these molecules cannot be administered orally and often exert severe systemic toxicity when administered IV. Then, based on preliminary in vitro results, OBTAC is a drug-design project to develop novel amphiphilic peptoïdic polymers, as simplified orally-active AMP analogues, to treat C. difficile infections (CDI) at low industrial production costs. A consortium of 4 complementary partners, proposes a “hit-to-lead” pharmacochemistry approach involving i) structure-activity relationship studies, ii) optimization of the synthesis of monomers and of the polymerization process to decrease production cost and environmental impact, iii) exhaustive microbiological studies including in vivo evaluation on a mouse infectious model and iv) tritium labeling to allow biodistribution and pharmacokinetic evaluation in mouse, in order to identify an innovative orally-active pre-clinical antibiotic candidate against CDI with easy and low cost scale-up synthesis.