Exploration of energy–coupling factor transporters as a novel antimicrobial target
The global rise in antimicrobial resistance is an ongoing threat due to inability of common antibiotics to treat bacterial infections. Microbes can adapt and eventually evade treatments leading to the emergence of multidrug-resistance strains. Therefore, there is a need to discover new antimicrobial compounds with unique modes of action as well as novel targets. The energy-coupling factor (ECF) transporters are such a potential novel antimicrobial target.
ECF transporters are a family of transmembrane proteins that facilitate the uptake of crucial vitamins in bacteria and are upsent of humans. These features make ECF transporters very attractive targets for developing new antimicrobial compounds.The focus of Spyros Bousis's thesis is to provide evidence of the importance of ECF transporters and the identification and optimization of inhibitors against them.
First, Bousis presents an overview of ECF transporters as novel antimicrobial target protein alongside significant auxotrophic pathogens that depending on them. Then, Bousis describes the development of a novel functional cell-based assay to screen and validate inhibitors of ECF transporters. He also reports on a structure-guided optimization of small molecule inhibitors of ECF transporters, after a new ligand was recently discovered. Finally, Bousis describes the expression and characterization of the ECF transporter of pantothenate from Streptococcus pneumoniae. In addition, surface plasmon resonance assay (SPR) was used to screen inhibitors followed by a protein stability evaluation using a thermal shift assay.