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

Area of Science:

• Medicinal Chemistry
• Microbiology
• Pharmacology

Background:

• Antibiotic resistance is a global health crisis, with methicillin-resistant Staphylococcus aureus (MRSA) posing a significant threat for skin and soft tissue infections.
• The NorA efflux pump in S. aureus contributes to antibiotic resistance by actively removing antibacterial agents from the bacterial cell.
• Inhibiting the NorA efflux pump is a potential strategy to overcome antibiotic resistance and re-sensitize bacteria to existing drugs.

Purpose of the Study:

• To design, synthesize, and evaluate novel indole derivatives as inhibitors of the NorA efflux pump.
• To explore the impact of substitutions at the C5 and N1 positions of the indole scaffold on NorA efflux pump inhibition.
• To identify potent efflux pump inhibitor (EPI) candidates with potential for further development.

Main Methods:

• Synthesis of 48 novel indole-based compounds with modifications at C5 and N1 positions.
• In vitro testing of synthesized compounds against norA-overexpressing S. aureus strains.
• Determination of NorA efflux pump inhibitory activity using IC50 values.
• Preliminary assessment of ADME (absorption, distribution, metabolism, and excretion) properties.

Main Results:

• Four synthesized indole compounds demonstrated significant NorA efflux pump inhibitory activity, with IC50 values below 5.0 μM.
• These compounds represent promising candidates for efflux pump inhibitors (EPIs).
• Initial data on the ADME profiles of the lead compounds were obtained.

Conclusions:

• Novel indole derivatives targeting the NorA efflux pump are effective in inhibiting bacterial drug extrusion.
• The C5 and N1 positions of the indole scaffold are suitable for modifications to develop potent EPIs.
• The identified compounds warrant further investigation for their therapeutic potential against resistant bacterial infections.