N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Microbiology

Background:

• Leucyl-tRNA synthetase (LeuRS) is crucial for bacterial protein synthesis.
• Inhibiting bacterial LeuRS is a potential strategy for developing new antibiotics.
• E. coli LeuRS is a validated target for antibacterial drug discovery.

Purpose of the Study:

• To discover and characterize novel inhibitors of E. coli leucyl-tRNA synthetase.
• To investigate the structure-activity relationships of N-Leucinyl benzenesulfonamides.
• To evaluate the antibacterial potential of these inhibitors against Gram-negative pathogens.

Main Methods:

• Isothermal titration calorimetry (ITC) for measuring inhibitor binding affinity.
• Enzymatic assays to determine inhibitory potency and selectivity.
• Molecular docking studies for structure-activity relationship (SAR) analysis.
• Determination of minimum inhibitory concentrations (MIC) against bacterial strains.

Main Results:

• N-Leucinyl benzenesulfonamides were identified as potent inhibitors of E. coli LeuRS.
• ITC and docking studies elucidated binding thermodynamics and SAR.
• The compounds demonstrated high selectivity for E. coli LeuRS over S. aureus and human orthologues.
• The lead compound, N-leucinyl benzenesulfonamide (R=H), exhibited significant antibacterial activity (MIC = 8 μg/mL) against E. coli.

Conclusions:

• N-Leucinyl benzenesulfonamides represent a promising new class of E. coli LeuRS inhibitors.
• The lead compound possesses favorable characteristics for further development as an antibacterial agent.
• This class of compounds offers a viable template for discovering novel antibiotics targeting Gram-negative bacteria.