Development of novel indole–quinoline hybrid molecules targeting bacterial proton motive force.

This article focuses on the development of novel synthetic antibacterials based on a CF3-substituted (hetero)aryl-quinoline hybrid scaffold aimed at improving drug development against antibiotic-resistant bacteria. Among 18 synthesized compounds, one designated 3m, containing a 1-methyl-1H-indole moiety, demonstrated potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria by disrupting the bacterial proton motive force (PMF), a key driver of ATP synthesis. The study showed that 3m's mechanism of PMF disruption is difficult for S. aureus to overcome and that 3m exhibits synergistic effects with colistin against Gram-negative bacteria with compromised outer membranes. Molecular dynamics simulations supported the role of the 1-methyl-1H-indole group in membrane incorporation, highlighting the scaffold's stability and editability for further pharmacokinetic and pharmacodynamic optimization.