Design and synthesis of thiamine analogues to study their binding to the ECF transporter for thiamine in bacteria

Energy-coupling factor (ECF) transporters mediate the uptake of vitamins in bacteria. Given that these ECF transporters are not present in eukaryotic cells, they represent an interesting target for the development of novel antibiotics. Here, we present the design and synthesis of compounds that bind to ThiT, the substrate-binding domain of the ECF transporter for thiamine from Lactococcus lactis . We modified the methyl substituent of the pyrimidine ring of thiamine, in order to evaluate its contribution to the binding affinity. Our results indicate that as long as a hydrophobic substituent is maintained, the high binding affinity is almost unchanged, opening up opportunities for the design of selective compounds. This work presents new small molecules that bind to the protein ThiT, which confers substrate specificity to the Energy-Coupling Factor (ECF) transporter for thiamine. Further development of the molecules may lead to compounds with antimicrobial activity.