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Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening
preprintsubmitted on 26.01.2020, 12:53 and posted on 27.01.2020, 12:51 by Eleonora Diamanti, Inda Setyawati, Spyridon Bousis, leticia mojas, lotteke Swier, Jörg Haupenthal, Paddy Gibson, carsten volz, weronika stanek, manuel Jaeger, jennifer herrmann, jan-willem veening, rolf müller, dirk J. slotboom, Anna K.H. Hirsch
Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.