Targeting the Energy-Coupling Factor Transporters: A Novel Antibiotic Drug Target in Streptococcus pneumoniae.

Energy-Coupling Factor (ECF) transporters are a hitherto underexplored target involved in the uptake of several micronutrients in bacteria and are absent in humans. Here, in Streptococcus pneumoniae, we demonstrate that the genes encoding ECF transporters are highly conserved and their expression is crucial for causing bacterial infection in both murine (in vivo) and human (ex vivo) infection models. Next, we demonstrated that the antimicrobial activity of our inhibitors against S. pneumoniae is related to the level of the ECF transporter expressed by the bacterium, confirming the target engagement of this chemical class in S. pneumoniae. The pharmacokinetic studies conducted revealed high peroral bioavailability for 4, which was also assessed in a murine neutropenic lung-infection model with S. pneumoniae, and observed a one log10 reduction in bacterial load compared to vehicle. This work sets the stage for an innovative approach to combat S. pneumonia-derived infections by targeting the ECF transporters with the novel chemotype reported.