Indole Based Weapons to Fight Antibiotic Resistance: A Structure–Activity Relationship Study

Antibiotic resistance represents
a worldwide concern, especially
regarding the outbreak of methicillin-resistant Staphylococcus
aureus, a common cause for serious skin and soft tissues
infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to
extrude selected antibacterial drugs and biocides from the membrane,
lowering their effective concentrations. Thus, the inhibition of NorA
represents a promising and challenging strategy that would allow recycling
of substrate antimicrobial agents. Among NorA inhibitors, the indole
scaffold proved particularly effective and suitable for further optimization.
In this study, some unexplored modifications on the indole scaffold
are proposed. In particular, for the first time, substitutions at
the C5 and N1 positions have been designed to give 48 compounds, which
were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor
(EPI) candidates. In addition, preliminary data on their ADME (absorption,
distribution, metabolism, and excretion) profile is reported.