Development of compounds with promising selective effects toward Helicobacter pylori flavodoxin

Resumen del póster presentado a la VII National Conference of the Institute for Biocomputation and Physics of Complex Systems (BIFI), celebrada en Zaragoza (España) del 4 al 6 de febrero de 2015.Helicobacter pylori (Hp) establishes life-long infections in the gastric mucosa of humans that may develop in a diversity of diseases from ulcer to cancer. Rising resistance of the bacteria to the antibiotics used in current treatments makes necessary the study of new therapies. A specific target of this bacteria is its flavodoxin protein (Hp-Fld), that is essential for its life. This protein exhibits a distinct pocket near the cofactor binding site, which could interact with selective organic compounds interfering with flavodoxin function2. We have recently developed, through organic synthesis, novel potential therapeutics based on one of the three molecules that we identified previously as avodoxin inhibitors. We expected these compounds to bind flavodoxin with a certain association constant, that is why we have monitored the binding of the inhibitors to Hp-Fld by isothermal titration calorimetry (ITC). In addition, we have tested these four novels analogous for cytotoxicity toward HeLa cells using both microscopy of living cells and cytotoxicity assays (XTT method). All of the new molecules show less toxicity toward HeLa cells than the original lead compounds. To establish their bactericidal effect, efficacy assays are currently in progress. These trials will allow us to establish whether these new compounds could represent promising selective inhibitors of the Helicobacter pylori flavodoxin, with the additional advantage of not generally perturbing the bacterial ora and not being yet counteracted by Hp resistance mechanisms.Peer Reviewe