Novel chiral phthalimides: Antimicrobial evaluation and docking study against Acinetobacter baumannii's OmpA protein

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• The rise of multi-drug-resistant (MDR) bacterial infections, particularly Acinetobacter baumannii, poses a significant threat to public health, potentially leading to a post-antibiotic era.
• Acinetobacter baumannii is a high-mortality pathogen with limited treatment options, necessitating the development of novel therapeutic strategies.
• Outer membrane protein A (OmpA) is a critical factor in antibiotic resistance in Acinetobacter baumannii, making it a promising drug target.

Purpose of the Study:

• To investigate the potential of chiral phthalimides as novel therapeutic agents against multi-drug-resistant Acinetobacter baumannii.
• To identify and evaluate specific chiral phthalimide compounds targeting the Outer membrane protein A (OmpA) of Acinetobacter baumannii.

Main Methods:

• Molecular docking simulations were employed to assess the binding affinity of three chiral phthalimide compounds (FIA, FIC, FII) with the OmpA protein.
• Molecular dynamics (MD) simulations were conducted to further validate the stability and binding efficacy of the compounds with OmpA.
• Antimicrobial activity was evaluated using the agar well diffusion method and minimum inhibitory concentration (MIC) assays.
• In vitro cytotoxicity was assessed by evaluating hemolytic activity against human red blood cells.

Main Results:

• All three tested chiral phthalimides (FIA, FIC, FII) demonstrated strong interactions with the OmpA protein, confirmed by molecular docking and MD simulations.
• Compound FIA exhibited the most significant antimicrobial activity, with an optimal zone of inhibition of 24 mm and a low MIC of 11 μg/μL against Acinetobacter baumannii.
• The tested compounds showed no hemolytic activity against human red blood cells, indicating favorable in vitro safety profiles.

Conclusions:

• Chiral phthalimides, particularly FIA, are effective against multi-drug-resistant Acinetobacter baumannii by targeting the OmpA protein.
• FIA demonstrates superior efficacy and a favorable safety profile compared to FIC and FII, positioning it as a promising candidate for further development.
• These findings suggest that chiral phthalimides hold significant potential as alternative therapeutic options for treating challenging Acinetobacter baumannii infections in the face of escalating antibiotic resistance.