Inhibitors of ECF transporters as novel antibacterial agents

Objetivo

Antimicrobial resistance is a global health threat, urgently calling for the development of novel anti-infective strategies. We will adopt a multidisciplinary approach to design, synthesize and optimize derivatives targeting ECF transporters as antibacterial agents. The ECF transporters are transmembrane proteins involved in the uptake of vitamins predominantly in Gram-positive pathogens (e.g. Streptococcus pneumoniae, Enterococcus faecalis, E. faecium, Staphylococcus aureus). Their inhibition prevents the uptake of vitamins from the environment, leading to starvation followed by cell death. Due to their critical role in the homeostasis of vitamins in bacteria as well as their absence in humans, ECF transporters are considered a promising novel antimicrobial target. We will thoroughly profile our inhibitors for their in vitro on-target and antibacterial activities. We will, on the one hand, further validate the cellular target through advanced target engagement studies and attempt to achieve a co-crystal structure using cryo-electron microscopy. Furthermore, evaluation of the inhibitors for their in vitro ADME-T properties and in vivo pharmacokinetic profiles will set the stage for in vivo infection models in mice. The extensive data that we will gather will enable us to nominate the most promising compound(s) for further multiparameter optimization en route to the nomination of a preclinical candidate. Ultimately, this opens access to novel anti-infectives with an unprecedented mode of action.